Approach to the patient with abnormal liver biochemical and function testsAuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jan 21, 2015.

INTRODUCTION — Abnormal liver biochemical and function tests are frequently detected in

asymptomatic patients since many screening blood test panels routinely include them [1]. A

population-based survey in the United States conducted between 1999 and 2002 estimated that

an abnormal alanine aminotransferase (ALT) was present in 8.9 percent of respondents.

Although the term "liver function tests" (LFTs) is used commonly, it is imprecise since many of

the tests reflecting the health of the liver are not direct measures of its function. Furthermore,

the commonly used liver biochemical tests may be abnormal even in patients with a healthy

liver. However, for the sake of simplicity, the abbreviation "LFTs" will be used in this discussion

to denote liver biochemical and function tests in general.

This topic review will provide an overview on the evaluation of patients with abnormal liver

biochemical and function tests. Detailed discussions of the individual tests are presented

separately. (See "Liver biochemical tests that detect injury to hepatocytes" and "Enzymatic

measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl

transpeptidase)" and "Classification and causes of jaundice or asymptomatic

hyperbilirubinemia" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation

factors, prothrombin time)".)

COMMON LIVER BIOCHEMICAL AND FUNCTION TESTS — Blood tests commonly obtained

to evaluate the health of the liver include liver enzyme levels, tests of hepatic synthetic function,

and the serum bilirubin level. Elevations of liver enzymes often reflect damage to the liver or

biliary obstruction, whereas an abnormal serum albumin or prothrombin time may be seen in the

setting of impaired hepatic synthetic function. The serum bilirubin in part measures the liver's

ability to detoxify metabolites and transport organic anions into bile.

Liver enzymes — Liver enzymes that are commonly measured in the serum include:

●Serum aminotransferases: alanine aminotransferase (ALT, formerly called SGPT) and

aspartate aminotransferase (AST, formerly called SGOT)

●Alkaline phosphatase

●Gamma-glutamyl transpeptidase (GGT)

●5'-nucleotidase

●Lactate dehydrogenase (LDH)

Aminotransferases — The sensitivity and specificity of the serum aminotransferases

(particularly serum ALT) for differentiating those with liver disease from those without liver

disease depend on the cutoff values chosen to define an abnormal test. A population-based

study from the US National Health and Nutrition Examination Survey examined patients with

known hepatitis C virus infection (n = 259) and compared them with patients at low risk of liver

injury (n = 3747) to determine optimal cutoff values for ALT [2]. The optimal cutoff for men was

an ALT of 29 int. unit/L and for women was an ALT of 22 int. unit/L. (See "Liver biochemical

tests that detect injury to hepatocytes", section on 'Serum aminotransferases'.)

ALT levels correlate with the degree of abdominal adiposity [3], and at least two large studies

suggested that the cutoff values should be adjusted for gender and body mass index [4,5].

However, most patients identified using the lower cutoff values had only mild liver disease or no

identifiable cause of the abnormal laboratory values. Thus, the overall benefit of the proposed

modifications is unclear since it would translate into a large increase in the absolute number of

patients who would require evaluation for an uncertain clinical benefit [6].

There is also wide variability of what is considered to be the upper limit of normal for ALT across

different laboratories [7]. This is likely due to the various reference standards used for different

chemical analyzers or in different laboratories. Thus, comparing values across different

laboratories may not be straightforward.

Alkaline phosphatase — Serum alkaline phosphatase is derived predominantly from the liver

and bones. An elevated alkaline phosphatase can be fractionated to determine if it originates

from the liver or bones, though more often a liver source is confirmed by the simultaneous

elevation of other measures of cholestasis (eg, gamma-glutamyl transpeptidase).

(See 'Confirming an elevated alkaline phosphatase is of hepatic origin' below.)

Other sources may also contribute to serum levels of alkaline phosphatase. Women in the third

trimester of pregnancy, for example, have elevated serum alkaline phosphatase levels due to an

influx into blood of placental alkaline phosphatase. Individuals with blood types O and B can

have elevated serum alkaline phosphatase levels after eating a fatty meal due to an influx of

intestinal alkaline phosphatase. Infants and toddlers occasionally display transient marked

elevations of alkaline phosphatase in the absence of detectable bone or liver disease. Alkaline

phosphatase elevations have been noted in patients with diabetes mellitus [8]. There are also

reports of a benign familial occurrence of elevated serum alkaline phosphatase due to intestinal

alkaline phosphatase. (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-

nucleotidase, gamma-glutamyl transpeptidase)", section on 'Alkaline

phosphatase' and "Transient hyperphosphatasemia of infancy and early childhood".)

Alkaline phosphatase levels also vary with age. Alkaline phosphatase levels are generally

higher in children and adolescents because of physiologic osteoblastic activity. Levels may be

up to three times higher than in healthy adults, with maximum levels in infancy and

adolescence, coinciding with periods of maximum bone growth velocity (figure 1). Also, the

normal serum alkaline phosphatase level gradually increases from age 40 to 65 years,

particularly in women. The normal alkaline phosphatase level for an otherwise healthy 65-year-

old woman is more than 50 percent higher than that for a healthy 30-year-old woman.

Gamma-glutamyl transpeptidase — GGT is found in hepatocytes and biliary epithelial cells,

as well as in the kidney, seminal vesicles, pancreas, spleen, heart, and brain. In normal full-term

neonates, serum GGT activity is six to seven times the upper limit of the adult reference range;

levels decline and reach adult levels by five to seven months of age [9]. (See "Enzymatic

measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl

transpeptidase)", section on 'Gamma-glutamyl transpeptidase'.)

5'-nucleotidase — 5'-nucleotidase is found in the liver, intestine, brain, heart, blood vessels,

and endocrine pancreas, but it is only released into serum by hepatobiliary tissue. Although its

physiologic function is unknown, 5'-nucleotidase specifically catalyzes hydrolysis of nucleotides

such as adenosine 5'-phosphate and inosine 5'-phosphate, in which the phosphate is attached

to the 5 position of the pentose moiety. (See "Enzymatic measures of cholestasis (eg, alkaline

phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)", section on '5'-Nucleotidase'.)

Lactate dehydrogenase — Lactate dehydrogenase (LDH) is commonly obtained when liver

biochemical tests are being checked. LDH is a cytoplasmic enzyme present in tissues

throughout the body (table 1). Five isoenzyme forms of LDH are present in serum and can be

separated by various electrophoretic techniques. The slowest migrating band predominates in

the liver [10,11]. This test is not as sensitive as the serum aminotransferases in liver disease

and has poor diagnostic specificity, even when isoenzyme analysis is used. It is more useful as

a marker of myocardial infarction and hemolysis [10]. (See "Biomarkers suggesting cardiac

injury other than troponins and creatine kinase".)

Function tests — Tests of hepatic synthetic function include:

●Serum albumin

●Prothrombin time/international normalized ratio (INR)

Reference ranges — Liver test reference ranges will vary from laboratory to laboratory. As an

example, one hospital's normal reference ranges for adults are as follows [12]:

●Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)

●Alkaline phosphatase

•Male: 45 to 115 int. unit/L

•Female: 30 to 100 int. unit/L

●Alanine aminotransferase (ALT):

•Male: 10 to 55 int. unit/L

•Female: 7 to 30 int. unit/L

●Aspartate aminotransferase (AST):

•Male: 10 to 40 int. unit/L

•Female: 9 to 32 int. unit/L

●Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)

●Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)

●Gamma-glutamyl transpeptidase (GGT)

•Male: 8 to 61 int. unit/L

•Female: 5 to 36 int. unit/L

●Prothrombin time (PT): 11.0 to 13.7 seconds

However, studies suggest that the optimal cutoff for ALT should be lower than the upper limits

used by many laboratories (ie, it should be approximately 30 int. unit/L for men and 20

int. unit/L for women). (See 'Aminotransferases' above.)

INITIAL EVALUATION — The initial evaluation of a patient with abnormal liver biochemical and

function tests (LFTs) includes obtaining a history to identify potential risk factors for liver disease

and performing a physical examination to look for clues to the etiology and for signs of chronic

liver disease. Subsequent testing is determined based on the information gathered from the

history and physical examination as well as the pattern of LFT abnormalities. (See 'Patterns of

LFT abnormalities' below.)

History — A thorough medical history is central to the evaluation of a patient with abnormal

LFTs. The history should determine if the patient has had exposure to any potential

hepatotoxins (including alcohol and medications), is at risk for viral hepatitis, has other disorders

that are associated with liver disease, or has symptoms that may be related to the liver disease

or a possible predisposing condition.

Alcohol consumption is a common cause of liver disease, though getting an accurate history

can be difficult. Several definitions have been proposed for what constitutes significant alcohol

consumption [13]. We define significant alcohol consumption as an average consumption of

>210 grams of alcohol per week in men or >140 grams of alcohol per week in women over at

least a two-year period, a definition that is consistent with a 2012 joint guideline from the

American Gastroenterological Association, the American Association for the Study of Liver

Diseases, and the American College of Gastroenterology [14]. A standard drink (360 mL [12 oz]

of beer, 150 mL [5 oz] of wine, or 45 mL 1.5 oz] of 80-proof spirits) contains approximately 14

grams of alcohol. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and

alcoholic cirrhosis", section on 'Diagnosis'.)

Questioning about drug use should seek to identify all drugs used, the amounts ingested, and

the durations of use. Drug use is not limited to prescription medications, but also includes over-

the-counter medications, herbal and dietary supplements, and illicit drug use. Features that

suggest drug toxicity include lack of illness prior to ingesting the drug, clinical illness or

biochemical abnormalities developing after beginning the drug, and improvement after the drug

is withdrawn. If an immunologic reaction is suspected, the illness will generally recur upon

reintroduction of the offending substance. However, rechallenge is not advised. (See "Drug-

induced liver injury" and "Hepatotoxicity due to herbal medications and dietary supplements".)

Risk factors for viral hepatitis include potential parenteral exposures (eg, intravenous drug use,

blood transfusion prior to 1992), travel to areas endemic for hepatitis, and exposure to patients

with jaundice. Hepatitis B and C are transmitted parenterally, whereas hepatitis A and E are

transmitted from person to person via a fecal-oral route (often via contaminated food). Hepatitis

E is uncommon in Europe and the United States, but it should be considered in patients who

live in or have travelled to Asia, Africa, the Middle East, or Central America.

(See "Epidemiology, transmission, and prevention of hepatitis B virus

infection" and "Epidemiology and transmission of hepatitis C virus infection" and "Overview of

hepatitis A virus infection in adults" and "Hepatitis E virus infection".)

Patients should be asked about conditions that are associated with hepatobiliary disease, such

as right-sided heart failure (congestive hepatopathy), diabetes mellitus and obesity

(nonalcoholic fatty liver disease), pregnancy (gallstones), inflammatory bowel disease (primary

sclerosing cholangitis, gallstones), early onset emphysema (alpha-1 antitrypsin deficiency),

celiac disease, and thyroid disease. (See "Congestive hepatopathy" and "Epidemiology, clinical

features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Association with

other disorders' and "Epidemiology of and risk factors for gallstones", section on 'Risk factors'.)

Finally, patients should be questioned about occupational or recreational exposure to

hepatotoxins (eg, mushroom picking). Examples of hepatitis due to exposures to hepatotoxins

include industrial chemicals such as vinyl chloride and the mushrooms Amanita

phalloides and Amanita verna, which contain a potent hepatotoxin (amatoxin). (See "Amatoxin-

containing mushroom poisoning including ingestion of Amanita phalloides".)

Physical examination — The physical examination may suggest the presence of chronic liver

disease and it may point to the underlying cause of the liver disease.

●Temporal and proximal muscle wasting suggest longstanding disease

●Stigmata of liver disease include spider nevi, palmar erythema, gynecomastia, and caput

medusae

●Ascites or hepatic encephalopathy may be seen in patients with decompensated cirrhosis

●Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are

commonly seen in advanced alcoholic cirrhosis and occasionally in other types of cirrhosis

●An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister

Mary Joseph's nodule) suggest an abdominal malignancy

●Increased jugular venous pressure, a sign of right-sided heart failure, suggests hepatic

congestion

●A right pleural effusion, in the absence of clinically apparent ascites, may be seen in

advanced cirrhosis

●Neurologic signs and symptoms may be seen in patients with Wilson disease

The abdominal examination should focus on the size and consistency of the liver, the size of the

spleen (a palpable spleen is enlarged), and an assessment for ascites (usually by determining

whether there is a fluid wave, shifting dullness, or bulging of the flanks). Patients with cirrhosis

may have an enlarged left lobe of the liver (which can be felt below the xiphoid) and an enlarged

spleen (which is most easily appreciated with the patient in the right lateral decubitus position).

A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An

enlarged, tender liver could be due to viral or alcoholic hepatitis or, less often, an acutely

congested liver secondary to right-sided heart failure or Budd-Chiari syndrome [15]. Severe right

upper quadrant tenderness with a positive Murphy's sign (respiratory arrest on inspiration while

pressing on the right upper quadrant) suggests cholecystitis or, occasionally, ascending

cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with

peritoneal spread.

Laboratory tests — The pattern of LFT abnormalities may suggest that the underlying cause of

the patient's liver disease is primarily the result of hepatocyte injury (elevated

aminotransferases) or cholestasis (elevated alkaline phosphatase). In addition, the magnitude of

the LFT abnormalities and the ratio of the aspartate aminotransferase (AST) to alanine

aminotransferase (ALT) may make certain diagnoses more or less likely.

Patterns of LFT abnormalities — LFT abnormalities can often be grouped into one of several

patterns: hepatocellular, cholestatic, or isolated hyperbilirubinemia. In addition, the

abnormalities may be acute or chronic based on whether they have been present for more

(chronic) or less (acute) than six months.

●Hepatocellular pattern:

•Disproportionate elevation in the serum aminotransferases compared with the

alkaline phosphatase

•Serum bilirubin may be elevated

•Tests of synthetic function may be abnormal

●Cholestatic pattern:

•Disproportionate elevation in the alkaline phosphatase compared with the serum

aminotransferases

•Serum bilirubin may be elevated

•Tests of synthetic function may be abnormal

●Isolated hyperbilirubinemia: As the name implies, patients with isolated

hyperbilirubinemia have an elevated bilirubin level with normal serum aminotransferases

and alkaline phosphatase

Because the serum bilirubin can be prominently elevated in both hepatocellular and cholestatic

conditions, it is not necessarily helpful in differentiating between the two. Common

hepatocellular diseases associated with an elevated bilirubin and jaundice include viral and toxic

hepatitis (including drugs, herbal therapies and alcohol) and end-stage cirrhosis from any cause

(table 2).

If both the serum aminotransferases and alkaline phosphatase are elevated, the LFT

abnormalities are characterized by the predominant abnormality (eg, if the serum

aminotransferases are 10 times the upper limit of normal and the alkaline phosphatase is twice

the upper limit of normal, the LFT abnormalities would be characterized as primarily

hepatocellular). However, making this distinction is not always possible. The degree of

aminotransferase elevation can occasionally help in differentiating between hepatocellular and

cholestatic processes. While ALT and AST values less than eight times the upper limit of normal

may be seen in either hepatocellular or cholestatic liver disease, values 25 times the upper limit

of normal or higher are seen primarily in hepatocellular diseases.

Abnormal tests of synthetic function may be seen with both hepatocellular injury and

cholestasis. A low albumin suggests a chronic process, such as cirrhosis or cancer, while a

normal albumin suggests a more acute process, such as viral hepatitis or choledocholithiasis. A

prolonged prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and

intestinal malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the

prothrombin time to correct with parenteral administration of vitamin K suggests severe

hepatocellular injury. (See "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation

factors, prothrombin time)".)

AST to ALT ratio — Most causes of hepatocellular injury are associated with an AST that is

lower than the ALT. An AST to ALT ratio of 2:1 or greater is suggestive of alcoholic liver

disease, particularly in the setting of an elevated gamma-glutamyl transpeptidase [16]. In a

study of 271 patients with biopsy-confirmed liver disease, more than 90 percent of the patients

whose AST to ALT ratio was two or greater had alcoholic liver disease [17]. The percentage

increased to greater than 96 percent when the ratio was greater than three. In addition, 70

percent of the patients with known alcoholic liver disease had an AST to ALT ratio greater than

two. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic

cirrhosis", section on 'Liver test abnormalities'.)

However, the AST to ALT ratio is occasionally elevated in an alcoholic liver disease pattern in

patients with nonalcoholic steatohepatitis, and it is frequently elevated in an alcoholic liver

disease pattern in patients with hepatitis C who have developed cirrhosis. In addition, patients

with Wilson disease or cirrhosis due to viral hepatitis may have an AST that is greater than the

ALT, though in patients with cirrhosis the ratio typically is not greater than two. (See "Wilson

disease: Clinical manifestations, diagnosis, and natural history", section on 'Hepatic disease'.)

Magnitude of AST and ALT elevations — The magnitude of AST and ALT elevations vary

depending on the cause of the hepatocellular injury [18-21]. While values may vary in individual

patients, the following are typical AST and ALT patterns:

●Alcoholic fatty liver disease: AST <8 times the upper limit of normal; ALT <5 times the

upper limit of normal

●Nonalcoholic fatty liver disease: AST and ALT <4 times the upper limit of normal

●Acute viral hepatitis or toxin-related hepatitis with jaundice: AST and ALT >25 times the

upper limit of normal

●Ischemic hepatopathy (ischemic hepatitis, shock liver): AST and ALT >50 times the

upper limit of normal (in addition the lactate dehydrogenase is often markedly elevated)

●Chronic hepatitis C virus infection: Wide variability, typically normal to less than twice the

upper limit of normal, rarely more than 10 times the upper limit of normal

●Chronic hepatitis B virus infection: Levels fluctuate; the AST and ALT may be normal,

though most patients have mild to moderate elevations (approximately twice the upper

limit of normal); with exacerbations, levels are more than 10 times the upper limit of normal

Other laboratory abnormalities — Patients with Wilson disease may have a Coombs-negative

hemolytic anemia, a ratio of alkaline phosphatase (int. unit/L) to total bilirubin(mg/dL) of less

than two, or a normal/subnormal alkaline phosphatase. (See "Wilson disease: Clinical

manifestations, diagnosis, and natural history", section on 'Hepatic disease'.)

ELEVATED SERUM AMINOTRANSFERASES — In the setting of hepatocyte damage, alanine

aminotransferase (ALT) and aspartate aminotransferase (AST) are released from hepatocytes,

leading to increased serum levels. The differential diagnosis for elevated serum

aminotransferases is broad and includes viral hepatitis, hepatotoxicity from drugs or toxins,

alcoholic liver disease, ischemic hepatopathy, and malignant infiltration. The evaluation should

take into account the patient's risk factors for liver disease as well as findings from the physical

examination that may point to a particular diagnosis. (See 'History' above and 'Physical

examination' above.)

Acute liver failure — Acute liver failure is characterized by acute hepatocellular injury with

LFTs typically more than 10 times the upper limit of normal, hepatic encephalopathy, and a

prolonged prothrombin time. The evaluation of patients with acute liver failure is discussed in

detail elsewhere. (See "Acute liver failure in adults: Etiology, clinical manifestations, and

diagnosis", section on 'Diagnosis'.)

Marked elevation without liver failure — Patients with marked elevations in their liver function

tests (approximately 15 times the upper limit of normal or higher) often have acute hepatitis,

though in some cases, there may be underlying chronic liver disease (eg, Wilson disease or an

acute exacerbation of hepatitis B virus).

Differential diagnosis — Marked elevations in serum aminotransferase levels may be seen

with:

●Acetaminophen (paracetamol)

●Idiosyncratic drug reactions (table 3)

●Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus;

Epstein-Barr virus; cytomegalovirus) or an acute exacerbation of chronic viral hepatitis

(hepatitis B)

●Alcoholic hepatitis

●Autoimmune hepatitis

●Wilson disease

●Ischemic hepatopathy

●Budd-Chiari syndrome

●Sinusoidal obstruction syndrome (veno-occlusive disease)

●HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally

acute fatty liver of pregnancy

●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma,

melanoma, or myeloma)

●Partial hepatectomy

●Toxin exposure, including mushroom poisoning

●Sepsis

●Heat stroke

●Muscle disorders (acquired muscle disorders [eg, polymyositis], seizures, and heavy

exercise [eg, long distance running])

Evaluation of markedly elevated aminotransferases — For patients with marked elevations

of serum aminotransferases, we obtain the following laboratory tests:

●Acetaminophen level

●Toxicology screen

●Acute viral hepatitis serologies

•IgM anti-hepatitis A

•Hepatitis B surface antigen and IgM anti-hepatitis B core

•Anti-hepatitis C virus antibody, hepatitis C RNA

•In some cases (based on patient history and risk factors): anti-herpes simplex virus

antibodies, anti-varicella zoster antibodies, anti-CMV antibodies, CMV antigen, and,

for Epstein-Barr virus, a complete blood count and monospot

●Serum pregnancy test in women of child-bearing potential who are not already known to

be pregnant

●Autoimmune markers (antinuclear antibodies, anti-smooth muscle

antibodies, anti-liver/kidney microsomal antibodies type 1, immunoglobulin levels)

●Transabdominal ultrasonography with Doppler imaging to look for evidence of vascular

occlusion (eg, Budd-Chiari syndrome)

Additional tests that are indicated in specific circumstances include:

●Ceruloplasmin level in patients suspected of having Wilson disease. (See "Wilson

disease: Clinical manifestations, diagnosis, and natural history", section on 'When to

consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and

natural history", section on 'Diagnosis'.)

●Hepatitis D virus antibodies in patients with acute or chronic hepatitis B. (See "Diagnosis

of hepatitis D virus infection", section on 'Diagnosis of HDV infection'.)

●Hepatitis E virus antibodies in patients who live in or travel to areas endemic for hepatitis

E, such as Asia, Africa, the Middle East, and Central America or in patients who are

pregnant (because of the high rates of acute liver failure in pregnant women with hepatitis

E). Additionally, cases of hepatitis E in the absence of foreign travel have been reported

increasingly in developed countries [22,23], and it is reasonable to test for antibodies to

hepatitis E virus if no other cause for the elevated aminotransferases is found.

(See "Hepatitis E virus infection", section on 'Diagnosis'.)

●Urinalysis to look for proteinuria in women who are pregnant. (See "Preeclampsia:

Clinical features and diagnosis", section on 'Diagnosis'.)

●Serum creatinine kinase or aldolase in patients with risk factors for or symptoms of

muscle disorders.

If the above testing is negative, we typically proceed with a liver biopsy if the acute elevation of

the serum aminotransferases fails to resolve or decline, or if the patient appears to be

developing acute liver failure. If the elevation is less than five times the upper limit of normal and

the patient appears well, we may follow the patient expectantly, checking liver tests every three

to six months.

Mild to moderate elevation — Mild to moderate elevations of the serum aminotransferases

(less than 15 times the upper limit of normal) are often seen with chronic liver disease, though

transient elevations may also be seen in patients with mild hepatic insults (eg, intake of nontoxic

doses of acetaminophen).

Differential diagnosis — Conditions associated with mild to moderate serum aminotransferase

elevations include (table 4):

●Medication use (table 3)

●Chronic viral hepatitis (hepatitis B, C)

●Alcoholic liver disease

●Hemochromatosis

●Nonalcoholic fatty liver disease

●Autoimmune hepatitis

●Wilson disease

●Alpha-1 antitrypsin deficiency

●Congestive hepatopathy

●Adult bile ductopenia

●Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma,

melanoma, or myeloma)

●Muscle disorders (eg, subclinical inborn errors of muscle metabolism)

●Thyroid disorders

●Celiac disease

●Adrenal insufficiency

●Anorexia nervosa

●Macro AST (moderate elevations in plasma AST levels due to the presence AST-

immunoglobulin complexes, usually IgG) [24]

Evaluation of mildly or moderately elevated aminotransferases — The initial evaluation of

patients with mildly to moderately elevated serum aminotransferases includes testing for chronic

viral hepatitis, hemochromatosis, and nonalcoholic fatty liver disease (table 5). The majority of

patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing

will have alcoholic liver disease, steatosis, or steatohepatitis [25,26].

We typically start the evaluation of patients LFTs that are 2 to less than 10 times the upper limit

of normal with the following:

●Hepatitis B – Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core

antibody. (See "Diagnosis of hepatitis B virus infection".)

●Hepatitis C – Hepatitis C antibody. (See "Diagnosis and evaluation of chronic hepatitis C

virus infection".)

●Hemochromatosis – Serum iron and total iron binding capacity (TIBC) with calculation of

transferrin saturation (serum iron/TIBC). A transferrin saturation greater than 45 percent

warrants obtaining a serum ferritin. Ferritin should not be obtained as an initial test

because it is an acute phase reactant and therefore less specific than the transferrin

saturation. A serum ferritin concentration of greater than 400 ng/mL (900 pmol/L) in men

and 300 ng/mL (675 pmol/L) in women further supports the diagnosis of

hemochromatosis. (See "Approach to the patient with suspected iron overload", section on

'Making the diagnosis of iron overload'.)

●Nonalcoholic fatty liver disease – The initial evaluation to identify the presence of fatty

infiltration of the liver is radiologic imaging, including ultrasonography, computed

tomography (CT), or magnetic resonance imaging (MRI). Ultrasonography has a lower

sensitivity than CT or MRI but is less expensive. (See "Epidemiology, clinical features, and

diagnosis of nonalcoholic fatty liver disease in adults".)

In a patient with a history of significant alcohol consumption, we generally do not obtain

additional testing if the above tests are negative. For patients with mild LFT elevations (less

than twice the upper limit of normal), we typically recheck the LFTs in six months and only

pursue the above workup if they remain elevated. (See 'History' above.)

If the initial evaluation fails to identify a likely source of the aminotransferase elevation, we test

for the following:

●Autoimmune hepatitis – Serum protein electrophoresis, and if positive, antinuclear

antibodies, anti-smooth muscle antibodies, and anti-liver/kidney microsomal antibodies

(see"Clinical manifestations and diagnosis of autoimmune hepatitis", section on

'Diagnosis')

●Thyroid disorders – Thyroid-stimulating hormone, free T4 concentration, free T3

concentration (see "Diagnosis of and screening for hypothyroidism in nonpregnant

adults" and"Diagnosis of hyperthyroidism")

●Celiac disease: Antibody screening with serum antiendomysial or tissue

transglutaminase antibodies (see "Diagnosis of celiac disease in adults")

If the source of the liver test abnormalities is still unclear, we test for the following:

●Wilson disease – Serum ceruloplasmin, evaluation for Kaiser-Fleisher rings, urinary

copper excretion (see "Wilson disease: Clinical manifestations, diagnosis, and natural

history", section on 'Initial evaluation')

●Alpha-1 antitrypsin deficiency – Serum alpha-1 antitrypsin level, alpha-1 antitrypsin

phenotyping (see "Clinical manifestations, diagnosis, and natural history of alpha-1

antitrypsin deficiency", section on 'Diagnosis')

●Adrenal insufficiency (in patients with symptoms associated with adrenal insufficiency,

such as chronic malaise, anorexia, or weight loss) – 8 AM serum cortisol and plasma

corticotropin (ACTH), and a high-dose ACTH stimulation test (see "Clinical manifestations

of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults")

●Muscle disorders (in patients with symptoms such exercise intolerance, muscle pain, or

muscle weakness) – Creatinine kinase or aldolase (see "Inborn errors of metabolism:

Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations')

A liver biopsy is often considered in patients in whom all of the above testing has been

unrevealing. However, in some settings, the best course may be expectant observation.

We suggest expectant observation in patients in whom the ALT and AST levels are less than

twice the upper limit of normal and no chronic liver condition has been identified by the above

noninvasive testing. We use a conservative estimate for the upper limit of normal for

aminotransferases (approximately 30 int. unit/L for men and 20 int. unit/L for women) since the

higher limits reported by many laboratories likely underestimate the degree of aminotransferase

elevation. In such patients, we will follow their liver biochemical and function tests every six

months. This approach was supported by a preliminary study in which expectant clinical follow-

up was found to be the most cost-effective strategy for managing asymptomatic patients with

negative viral, metabolic, and autoimmune markers and chronically elevated aminotransferases

[27]. A second small study also found that biopsy results rarely affected the management of

such patients [28].

We suggest a liver biopsy in patients in whom the ALT and AST are persistently greater than

twice the upper limit of normal. While it remains unlikely that the biopsy will provide a diagnosis

or lead to changes in management, it is often reassuring to the patient and clinician to know that

there is no serious disorder.

ELEVATED ALKALINE PHOSPHATASE — Cholestasis may develop in the setting of

extrahepatic or intrahepatic biliary obstruction (table 6). In patients with cholestasis, the alkaline

phosphatase is typically elevated to at least four times the upper limit of normal. The magnitude

of the serum alkaline phosphatase level does not distinguish extrahepatic cholestasis from

intrahepatic cholestasis. Lesser degrees of elevation are nonspecific and may be seen in many

other types of liver disease, such as viral hepatitis, infiltrative diseases of the liver, and

congestive hepatopathy. The gamma-glutamyl transpeptidase (GGT) may also be elevated in

the setting of cholestasis. However, elevated levels of serum GGT have been reported in a wide

variety of other conditions. Patients with a predominantly cholestatic pattern typically undergo a

right upper quadrant ultrasound to further characterize the cholestasis as intrahepatic or

extrahepatic.

Confirming an elevated alkaline phosphatase is of hepatic origin — If a patient has an

isolated elevation of the alkaline phosphatase, the first step in the evaluation is to confirm it is of

hepatic origin, since alkaline phosphatase can come from other sources, such as bone and

placenta (algorithm 1). If, however, there are other liver biochemical and function test (LFT)

abnormalities, particularly an elevated bilirubin, confirmation is typically not required.

To confirm an isolated elevation in the alkaline phosphatase is coming from the liver, a GGT

level or serum 5'-nucleotidase level should be obtained. These tests are usually elevated in

parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders.

An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt

an evaluation for bone diseases.

An elevated bone alkaline phosphatase is indicative of high bone turnover, which may be

caused by several disorders including healing fractures, osteomalacia, hyperparathyroidism,

hyperthyroidism, Paget disease of bone, osteogenic sarcoma, and bone metastases. We

generally refer such patients to an endocrinologist for evaluation. Initial testing may include

measurement of serum calcium, parathyroid hormone, 25-hydroxy vitamin D, and imaging with

bone scintigraphy. (See "Bone physiology and biochemical markers of bone turnover", section

on 'Markers of bone turnover' and "Clinical manifestations and diagnosis of Paget disease of

bone", section on 'Clinical manifestations' and "Clinical manifestations, diagnosis, and treatment

of osteomalacia", section on 'Diagnosis and evaluation'.)

Differential diagnosis — If the alkaline phosphatase elevation is isolated (ie, the other LFTs

are normal), is confirmed to be of hepatic origin, and persists over time, chronic cholestatic or

infiltrative liver diseases should be considered (table 6). The most common causes include

partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and

certain drugs, such as androgenic steroids and phenytoin. Infiltrative diseases include

sarcoidosis, other granulomatous diseases, amyloidosis, and less often, unsuspected cancer

that is metastatic to the liver.

Acute or chronic elevation of the alkaline phosphatase in conjunction with other LFT

abnormalities may be due to extrahepatic causes (eg, common bile duct stones, primary

sclerosing cholangitis, malignant biliary obstruction) or intrahepatic causes (eg, PBC, primary

sclerosing cholangitis, infiltrative disease). (See 'Extrahepatic cholestasis' below

and'Intrahepatic cholestasis' below.)

Evaluation of elevated alkaline phosphatase — Testing in patients with an elevated alkaline

phosphatase of hepatic origin typically starts with a right upper quadrant ultrasound to assess

the hepatic parenchyma and bile ducts.

The presence biliary dilatation on ultrasonography suggests extrahepatic cholestasis, whereas

the absence of biliary dilatation suggests intrahepatic cholestasis. However, ultrasonography

may fail to show ductal dilatation in the setting of extrahepatic cholestasis in patients with partial

obstruction of the bile duct or in patients with cirrhosis or primary sclerosing cholangitis, where

scarring prevents the intrahepatic ducts from dilating.

The subsequent evaluation depends on whether the ultrasound suggests extrahepatic

cholestasis or intrahepatic cholestasis. (See 'Extrahepatic cholestasis' below and 'Intrahepatic

cholestasis' below.)

Extrahepatic cholestasis — Although ultrasonography may indicate extrahepatic cholestasis,

it rarely identifies the site or cause of obstruction. The distal bile duct is a particularly difficult

area to visualize by ultrasonography because of overlying bowel gas. Potential causes of

extrahepatic cholestasis include (table 6):

●Choledocholithiasis (the most common cause) (see "Choledocholithiasis: Clinical

manifestations, diagnosis, and management", section on 'Imaging test characteristics')

●Malignant obstruction (pancreas, gallbladder, ampulla, or bile duct cancer) (see "Clinical

manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on

'Diagnostic approach' and "Gallbladder cancer: Epidemiology, risk factors, clinical

features, and diagnosis", section on 'Diagnostic evaluation' and "Ampullary carcinoma:

Epidemiology, clinical manifestations, diagnosis and staging", section on 'Diagnosis and

staging' and "Clinical manifestations and diagnosis of cholangiocarcinoma")

●Primary sclerosing cholangitis with an extrahepatic bile duct stricture (see "Primary

sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on

'Diagnosis')

●Chronic pancreatitis with stricturing of the distal bile duct (rare) (see "Complications of

chronic pancreatitis", section on 'Bile duct or duodenal obstruction')

●AIDS cholangiopathy (see "AIDS cholangiopathy", section on 'Diagnosis')

If ultrasonography suggests obstruction due to a stone or malignancy, or if the onset of the

cholestasis was acute, endoscopic retrograde cholangiopancreatography (ERCP) should be

carried out to confirm the diagnosis and, when possible, facilitate biliary drainage. If the

cholestasis is chronic, or in patients who are at high risk for ERCP, magnetic resonance

cholangiopancreatography (MRCP) or computed tomography (CT) should be obtained. ERCP

can then be performed if there is evidence of an obstructing stone, stricture, or malignancy. If

the results of ERCP or MRCP are negative for biliary tract disease, liver biopsy should be

considered. (See "Endoscopic retrograde cholangiopancreatography: Indications, patient

preparation, and complications", section on 'Indications for ERCP' and "Magnetic resonance

cholangiopancreatography" and "Magnetic resonance cholangiopancreatography", section on

'Clinical use'.)

Intrahepatic cholestasis — There are numerous possible causes of intrahepatic cholestasis

(table 6), including drug toxicity, PBC, primary sclerosing cholangitis, viral hepatitis, cholestasis

of pregnancy, benign postoperative cholestasis, infiltrative diseases, and total parenteral

nutrition. In many cases, a possible cause can be identified based on the patient's history. If

drug-induced cholestasis is suspected, elimination of the offending drug usually leads to

resolution of the cholestasis, though it may take months. If no cause is identified, additional

testing is required.

In patients with intrahepatic cholestasis, antimitochondrial antibodies (AMA) should be checked.

If present, AMA are highly suggestive of PBC, and a liver biopsy may be obtained to confirm the

diagnosis. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cirrhosis",

section on 'Diagnosis'.)

If AMA are absent, additional testing includes:

●MRCP to look for evidence of primary sclerosing cholangitis (see "Primary sclerosing

cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis')

●Testing for hepatitis A, B, C, and E (see 'Elevated serum aminotransferases' above)

●Testing for Epstein-Barr virus and cytomegalovirus (see "Infectious mononucleosis in

adults and adolescents", section on 'Diagnosis' and "Overview of diagnostic tests for

cytomegalovirus infection")

●Pregnancy testing in women of child bearing potential who are not known to be pregnant

(see "Intrahepatic cholestasis of pregnancy", section on 'Diagnosis')

If the above tests are negative and the alkaline phosphatase is persistently more than 50

percent above normal for more than six months, we obtain a liver biopsy. A liver biopsy may

reveal evidence of an infiltrative disease (eg, sarcoidosis or malignancy) or other causes of

cholestasis, such as vanishing bile duct syndrome and adult bile ductopenia. If the alkaline

phosphatase is less than 50 percent above normal, all of the other liver biochemical tests are

normal, and the patient is asymptomatic, we suggest observation alone since further testing is

unlikely to influence management [28].

ISOLATED GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT) ELEVATION — Elevated levels

of serum GGT have been reported in a wide variety of clinical conditions, including pancreatic

disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes

mellitus, and alcoholism. High serum GGT values are also found in patients taking medications

such as phenytoin and barbiturates. GGT is sensitive for detecting hepatobiliary disease, but its

usefulness is limited by its lack of specificity.

An elevated GGT with otherwise normal liver biochemical tests should not lead to an exhaustive

work-up for liver disease. We suggest GGT only be used to evaluate elevations of other serum

enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a

suspicion of alcohol abuse in a patient with an elevated AST and an AST to ALT ratio of greater

than 2:1). (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase,

gamma-glutamyl transpeptidase)".)

ISOLATED HYPERBILIRUBINEMIA — The initial step in evaluating a patient with an isolated

elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the

hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated

(indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from

overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in

conjugated bilirubin is due to decreased excretion into the bile ductules or leakage of the

pigment from hepatocytes into serum. (See "Clinical aspects of serum bilirubin

determination" and "Diagnostic approach to the adult with jaundice or asymptomatic

hyperbilirubinemia".)

Unconjugated (indirect) hyperbilirubinemia — Unconjugated hyperbilirubinemia may be

observed in a number of disorders (table 7). These can be divided into disorders associated

with bilirubin overproduction (such as hemolysis and ineffective erythropoiesis) and disorders

related to impaired hepatic uptake/conjugation of bilirubin (such as Gilbert's disease, Crigler-

Najjar syndrome, and the effects of certain drugs). The evaluation typically involves evaluation

for hemolytic anemia as well as obtaining a history to determine if the patient has Gilbert's

syndrome. In a patient with a history consistent with Gilbert's syndrome (eg, the development of

jaundice during times of stress) additional testing is not required. (See"Gilbert syndrome and

unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Diagnosis'.)

Hemolysis — Hemolysis can usually be detected by obtaining a reticulocyte count and serum

haptoglobin and examining the peripheral blood smear. Hemolytic disorders that cause

excessive heme production may be either inherited or acquired. Inherited disorders include

spherocytosis, sickle cell disease, and deficiency of red cell enzymes, such as pyruvate kinase

and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin rarely

exceeds 5 mg/dL (86 micromol/L). Higher levels may occur when there is coexistent renal or

hepatocellular dysfunction or acute hemolysis. (See "Approach to the diagnosis of hemolytic

anemia in the adult".)

Acquired hemolytic disorders include microangiopathic hemolytic anemia (eg, hemolytic-uremic

syndrome), paroxysmal nocturnal hemoglobinuria, and immune hemolysis. Ineffective

erythropoiesis occurs in cobalamin, folate, and iron deficiencies.

Impaired hepatic uptake or conjugation — Impaired hepatic uptake or conjugation of bilirubin

should be considered in the absence of hemolysis. This is most commonly caused by certain

drugs (including rifampicin and probenecid) that diminish hepatic uptake of bilirubin or by

Gilbert's syndrome (a common genetic disorder associated with unconjugated

hyperbilirubinemia). Much less commonly, indirect hyperbilirubinemia can be caused by two

other genetic disorders: Crigler-Najjar syndrome types I and II.

●Studies in Western populations have estimated that Gilbert's syndrome affects

approximately 3 to 7 percent of the population, with white males predominating over

females by a ratio of 2 to 7:1 [29]. Impaired conjugation of bilirubin is due to reduced

bilirubin uridine diphosphate (UDP) glucuronosyltransferase activity. Affected patients

have mild unconjugated hyperbilirubinemia with serum levels almost always less than

6 mg/dL (103 micromol/L). The serum levels may fluctuate, and jaundice is often identified

only during periods of illness or fasting. In an otherwise healthy adult with mildly elevated

unconjugated hyperbilirubinemia and no evidence of hemolysis, the presumptive diagnosis

of Gilbert's syndrome can be made without further testing. (See "Gilbert syndrome and

unconjugated hyperbilirubinemia due to bilirubin overproduction".)

●Crigler Najjar type I is an exceptionally rare condition found in neonates and is

characterized by severe jaundice (bilirubin >20 mg/dL [342 micromol/L]) and neurologic

impairment due to kernicterus. Crigler-Najjar type II is somewhat more common than type

I. Patients live into adulthood with serum bilirubin levels that range from 6 to

25 mg/dL (103 to 428micromol/L). Bilirubin UDP glucuronosyltransferase activity is

typically present but greatly reduced. Bilirubin UDP glucuronosyltransferase activity can be

induced by the administration of phenobarbital, which can reduce serum bilirubin levels in

these patients. (See "Crigler-Najjar syndrome".)

Conjugated (direct) hyperbilirubinemia — An isolated elevation in conjugated bilirubin is

found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Dubin-

Johnson syndrome and Rotor syndrome should be suspected in patients with mild

hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of

other abnormalities of standard liver biochemical tests. Normal levels of serum alkaline

phosphatase and GGT help to distinguish these conditions from disorders associated with

biliary obstruction. Differentiating between these syndromes is possible but clinically

unnecessary due to their benign nature. In children, other inherited disorders caused by

mutations of bile salt transporters may need to be considered [30]. (See "Inherited disorders

associated with conjugated hyperbilirubinemia".)

Patients with both conditions present with asymptomatic jaundice, typically in the second

decade of life. The defect in Dubin-Johnson syndrome is altered hepatocyte excretion of

bilirubin into the bile ducts, while Rotor syndrome appears to be due to defective hepatic

reuptake of bilirubin by hepatocytes [31].

ISOLATED ABNORMALITIES OF TESTS OF SYNTHETIC FUNCTION — Abnormalities in

tests of liver synthetic function, such as the prothrombin time and serum albumin level, are often

seen in patients with chronic liver disease in conjunction with other liver test abnormalities.

These patients should be evaluated according to the predominant pattern of LFT abnormalities.

(See 'Patterns of LFT abnormalities' above.)

However, isolated abnormalities in the prothrombin time or albumin are typically due to causes

other than liver disease. The evaluation of these abnormalities is discussed elsewhere.

(See "Clinical use of coagulation tests", section on 'Prothrombin time (PT)' and "Overview of

heavy proteinuria and the nephrotic syndrome" and "Protein-losing

gastroenteropathy" and"Malnutrition in children in resource-limited countries: Clinical

assessment", section on 'Protein-energy malnutrition'.)

WHEN TO REFER TO A SPECIALIST — Referral to a gastroenterologist or hepatologist

should be considered for patients with unexplained, persistent LFT elevations (≥2 times the

upper limit of normal for aminotransferases or 1.5 times the upper limit of normal for alkaline

phosphatase) and for patients who are being considered for liver biopsy. We use a conservative

estimate for the upper limit of normal for aminotransferases (approximately 30 int. unit/L for men

and 20 int. unit/L for women) since the higher limits reported by many laboratories likely

underestimate the degree of aminotransferase elevation. (See 'Aminotransferases' above.)

If the LFTs normalize or remain mildly elevated (<2 times the upper limit of normal for

aminotransferases or less than 1.5 times the upper limit of normal for alkaline phosphatase),

expectant management is reasonable in most cases. In such patients, we would follow their liver

biochemical and function tests every six months. It is reasonable to refer such patients to a

gastroenterologist or hepatologist if the LFTs remain elevated without a clear explanation, if they

subsequently increase, or if otherwise warranted by the specific features of the case.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain

language, at the 5th to 6th grade reading level, and they answer the four or five key questions a

patient might have about a given condition. These articles are best for patients who want a

general overview and who prefer short, easy-to-read materials. Beyond the Basics patient

education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10th to 12th grade reading level and are best for patients who want in-depth information

and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print

or e-mail these topics to your patients. (You can also locate patient education articles on a

variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient information: Toxic hepatitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Blood tests commonly obtained to evaluate the health of the liver include liver enzyme

levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline

phosphatase, gamma-glutamyl transferase), tests of hepatic synthetic function (albumin,

prothrombin time/international normalized ratio [INR]), and the serum bilirubin level.

(See'Common liver biochemical and function tests' above.)

●The initial evaluation of a patient with abnormal liver biochemical and function tests

(LFTs) includes obtaining a history to identify potential risk factors for liver disease and

performing a physical examination to look for clues to the etiology and for signs of chronic

liver disease. Subsequent testing is determined based on the information gathered from

the history and physical examination as well as the pattern of LFT abnormalities (table

5 and algorithm 1). (See 'Initial evaluation' above.)

●LFT abnormalities can often be grouped into one of several patterns: hepatocellular,

cholestatic, or isolated hyperbilirubinemia. Patients with a hepatocellular process generally

have a disproportionate elevation in the serum aminotransferases compared with the

alkaline phosphatase, while those with a cholestatic process have the opposite findings.

The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic

conditions and therefore is not necessarily helpful in differentiating between the two.

Abnormal tests of synthetic function may be seen with both hepatocellular injury and

cholestasis. (See 'Patterns of LFT abnormalities' above.)

●In the setting of hepatocyte damage, ALT and AST are released from hepatocytes,

leading to increased serum levels. The differential diagnosis for elevated serum

aminotransferases is broad and includes viral hepatitis, hepatotoxicity from drugs or toxins,

alcoholic liver disease, hepatic ischemia, and malignant infiltration. The evaluation should

take into account the patient's risk factors for liver disease as well as findings from the

physical examination that may point to a particular diagnosis. The evaluation often

involves testing for viral hepatitis and autoimmune disease (table 5). Occasionally, a liver

biopsy may be required. (See 'Elevated serum aminotransferases' above.)

●Cholestasis may develop in the setting of extrahepatic or intrahepatic biliary obstruction

(table 6). In patients with cholestasis, the alkaline phosphatase is typically elevated to at

least four times the upper limit of normal. Lesser degrees of elevation are nonspecific and

may be seen in many other types of liver disease, such as viral hepatitis, infiltrative

diseases of the liver, and congestive hepatopathy. Patients with a predominantly

cholestatic pattern typically undergo right upper quadrant ultrasonography to further

characterize the cholestasis as intrahepatic or extrahepatic. (See 'Elevated alkaline

phosphatase' above.)

The presence of biliary dilatation on ultrasonography suggests extrahepatic cholestasis

which may be due to gallstones, strictures, or malignancy. The absence of biliary dilatation

suggests intrahepatic cholestasis. There are numerous possible causes of intrahepatic

cholestasis (table 6), including drug toxicity, primary biliary cirrhosis, primary sclerosing

cholangitis, viral hepatitis, cholestasis of pregnancy, benign postoperative cholestasis,

infiltrative diseases, and total parenteral nutrition. Subsequent testing to identify the

underlying cause may include checking antimitochondrial antibodies, magnetic resonance

cholangiopancreatography, computed tomography, and/or endoscopic retrograde

cholangiopancreatography (algorithm 1). (See 'Evaluation of elevated alkaline

phosphatase' above.)

●The evaluation of isolated hyperbilirubinemia begins with determining whether the

hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated

(indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from

overproduction, impairment of uptake, or impaired conjugation of bilirubin. The evaluation

of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia as

well as obtaining a history to determine if the patient has Gilbert's syndrome. In a patient

with a history consistent with Gilbert's syndrome (eg, the development of jaundice during

times of stress) additional testing is not required. (See 'Isolated hyperbilirubinemia'above

and 'Unconjugated (indirect) hyperbilirubinemia' above.)

An isolated elevation in conjugated bilirubin is found in two rare inherited conditions:

Dubin-Johnson syndrome and Rotor syndrome. Dubin-Johnson syndrome and Rotor

syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-

reacting fraction of approximately 50 percent) in the absence of other abnormalities of

standard liver biochemical tests. Normal levels of serum alkaline phosphatase and GGT

help to distinguish these conditions from disorders associated with biliary obstruction.

Differentiating between these syndromes is possible but clinically unnecessary due to their

benign nature. (See 'Conjugated (direct) hyperbilirubinemia' above.)Liver biochemical tests that detect injury to hepatocytesAuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Dec 09, 2014.

INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.

The most common tests used in clinical practice include the serum aminotransferases, bilirubin,

alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver

function tests", although this term is somewhat misleading since most do not accurately reflect

how well the liver is functioning, and abnormal values can be caused by diseases unrelated to

the liver. In addition, these tests may be normal in patients who have advanced liver disease.

Several specialized tests have also been developed (such as indocyanine green clearance),

which, although uncommonly used in clinical practice, can measure specific aspects of hepatic

function.

Despite their limitations, liver biochemical and function tests have many applications in clinical

medicine:

●They provide a noninvasive method to screen for the presence of liver disease. The

serum aminotransferases, for example, are part of panel of tests used to screen all blood

donors in the United States for the presence of transmissible viruses.

●They can be used to measure the efficacy of treatments for liver disease (such as

immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:

Treatment".)

●They can be used to monitor the progression of a disease such as viral or alcoholic

hepatitis.

●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.

As an example, the Child-Turcotte-Pugh score (Child-Pugh class), which incorporates the

prothrombin time and serum bilirubin and albumin concentrations, can predict survival

(table 1).

The pattern of abnormalities on these tests is more accurate than any of the individual tests.

Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the

serum total bilirubin and alkaline phosphatase indicates cholestasis. Recognition of patterns that

are consistent with specific diseases can prompt appropriate additional testing.

The liver biochemical and function tests can be categorized as follows:

●Tests that detect injury to hepatocytes – Most of these tests measure the activity of

hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are

normally intracellular, but are released when hepatocytes are injured.

●Tests of the liver's capacity to transport organic anions and metabolize drugs – These

tests measure the liver's ability to clear endogenous or exogenous substances from the

circulation. The best studied include serum measurements of bilirubin, bile acids, caffeine,

and lidocaine metabolites, a variety of breath tests, and clearance tests such as

bromsulphalein (BSP) and indocyanine green (ICG).

●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess

the biosynthetic capacity of the liver are the serum albumin and the prothrombin time

(which requires the presence of clotting factors produced in the liver). Other tests which

have been use are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and

alpha-1 antitrypsin.

●Tests that detect chronic inflammation in the liver, altered immunoregulation, or viral

hepatitis – These tests include the immunoglobulins, hepatitis serologies, and specific

autoantibodies. Most of these substances are proteins made by B lymphocytes, not by

hepatocytes. However, some are quite specific for certain liver diseases, such as

antimitochondrial antibodies in primary biliary cirrhosis. (See "Clinical manifestations,

diagnosis, and prognosis of primary biliary cirrhosis".)

The liver contains thousands of enzymes, some of which are also present in serum in very low

concentrations. Elevation of an enzyme activity in the serum primarily reflects release from

damaged liver cells. Elevation of serum enzyme tests can be grouped into two categories:

●Enzymes that reflect generalized damage to hepatocytes

●Enzymes that reflect cholestasis

This topic will review the tests that detect injury to hepatocytes. The other categories and

enzymes that reflect cholestasis are discussed separately. (See "Enzymatic measures of

cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)

SERUM AMINOTRANSFERASES — The serum aminotransferases (formerly called

transaminases) are sensitive indicators of liver cell injury [1-3]. The most commonly measured

are alanine aminotransferase (ALT, serum glutamic-pyruvic transaminase [SGPT]) and

aspartate aminotransferase (AST, serum glutamic-oxaloacetic transaminase [SGOT]). These

enzymes catalyze the transfer of the alpha-amino groups of alanine and aspartate, respectively,

to the alpha-keto group of ketoglutarate, which results in the formation of pyruvate and

oxaloacetate.

The serum ALT and AST concentrations are normally less than 30 to 40 int. unit/L (0.5001 to

0.6668 microkatal/liter), although there is some debate as to the optimal cutoff values that

should be used. Several studies have shown that ALT levels are normally higher in men, and

vary directly with body mass index and to a lesser degree with serum lipid levels and age [4,5].

(See "Approach to the patient with abnormal liver biochemical and function tests", section on

'Common liver biochemical and function tests'.) Levels decline in frail older adults, and

consumption of coffee and especially caffeine may lower serum ALT levels by mechanisms that

are incompletely understood [6].

The source of these enzymes in serum has never been clearly established, although they

probably originate in tissues rich in ALT and AST. ALT is present in highest concentration in the

liver [7,8]. AST is found, in decreasing order of concentration, in the liver, cardiac muscle,

skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes and is less

specific than ALT for liver disease.

The location of the aminotransferases within cells is variable. ALT is found exclusively in the

cytosol, while AST occurs in the cytosol and mitochondria [8]. The cytosolic and mitochondrial

forms of AST are immunologically distinct isoenzymes, which can be distinguished by several

laboratory techniques [9]. Approximately 80 percent of AST activity in human liver is derived

from the mitochondrial isoenzyme [8]. In contrast, most of the circulating AST activity in healthy

people is derived from the cytosolic isoenzyme [7].

Neither ALT nor AST has isoenzymes that are tissue specific. As a result, isoenzyme analysis of

serum ALT or AST is of limited clinical utility. Exceptions to this general rule can occur in acute

myocardial infarction and chronic (but not acute) alcoholic liver disease [10,11]. Large increases

in mitochondrial AST occur in serum after extensive tissue necrosis and assay of mitochondrial

AST has been advocated as an accurate test for the detection of myocardial infarction [10].

However, other serum tests, such as troponins, are considered the standard for the diagnosis of

myocardial infarction. (See "Troponins and creatine kinase as biomarkers of cardiac injury".)

Measurement — The activity of the serum aminotransferases reflects the rate at which they

enter and are cleared from the circulation. An elevation in serum ALT and AST is usually related

to damage or destruction of tissues rich in the aminotransferases, or to changes in cell

membrane permeability that permit leakage into the circulation.

Clearance of the serum aminotransferases is similar to that of other proteins and involves

catabolism by the reticuloendothelial system; AST is cleared more rapidly than ALT [12]. The

major site of AST clearance is the hepatic sinusoidal cell [13]. It is unlikely that biliary or urinary

excretion has a significant role since the enzymes are virtually undetectable in the urine and

present in only very small amounts in bile [12,14].

Of the numerous methods developed for measuring ALT and AST activity in serum, the most

specific method involves the indirect measurement of lactate and malate (derived from the

formation of pyruvate and oxaloacetate, respectively, in the aminotransferase reactions) [10].

During this reaction, the reduced form of nicotinamide-adenine dinucleotide (NADH), (the

cofactor in the reaction) is oxidized to NAD. Because NADH, but not NAD, absorbs light at 340

nm, the event can be followed spectrophotometrically by the loss of absorptivity at 340 nm.

The serum aminotransferases may be falsely elevated or decreased under certain

circumstances. Drugs such as erythromycin and para-aminosalicylic acid may produced falsely

elevated aminotransferase values if older colorimetric tests are used [15]. In contrast, falsely low

serum AST (but not ALT) is seen in patients with renal failure [16]. This phenomenon is most

pronounced when the SMA-12/60 autoanalyser is used and presumably reflects interference

with the assay by a retained uremic toxin. Serum AST activity increases significantly after

hemodialysis, indicating removal of the inhibitor, which does not appear to be urea [16].

(See "Serum enzymes in patients with renal failure".) Subnormal values of serum ALT have

been described in patients with Crohn's disease, the reason for which is unclear [17].

Clinical significance — Serum aminotransferases are elevated in most liver diseases and in

disorders that involve the liver (such as various infections, acute and chronic heart failure, and

metastatic carcinoma). Elevations up to eight times the upper limit of normal are nonspecific and

may be found in any of the above disorders. The highest elevations occur in disorders

associated with extensive hepatocellular injury, such as acute viral hepatitis, ischemic hepatitis

(shock liver), and acute drug- or toxin-induced liver injury (eg,acetaminophen toxicity). The

evaluation of the serum aminotransferases in various clinical settings, including use of

the AST/ALT ratio, is discussed in detail separately. (See"Approach to the patient with abnormal

liver biochemical and function tests".)

The extent of liver cell necrosis correlates poorly with the magnitude of serum aminotransferase

elevation; in addition, the absolute elevation in serum aminotransferases is of little prognostic

value since the liver can recover from most forms of acute injury. There is, however, one pattern

that is important to recognize: a rapid decrease in plasma AST and ALT levels, together with a

rise in the plasma bilirubin concentration and prolongation of the prothrombin time, is indicative

of a poor prognosis in patients with acute liver failure. Although a rapid decrease in serum

aminotransferases is usually a sign of recovery from disease, it may also reflect the massive

destruction of viable hepatocytes in patients with acute liver failure, signaling a poor prognosis.

SERUM CONCENTRATIONS OF OTHER HEPATIC ENZYMES — A variety of other hepatic

enzymes have been measured but none is as useful as the aminotransferases for the diagnosis

of hepatic disease.

Lactate dehydrogenase — Lactate dehydrogenase (LDH) is a cytoplasmic enzyme present in

tissues throughout the body (table 2). Five isoenzyme forms of LDH are present in serum and

can be separated by various electrophoretic techniques. The slowest migrating band

predominates in the liver [18,19]. This test is not as sensitive as the serum aminotransferases in

liver disease and has poor diagnostic specificity, even when isoenzyme analysis is used. It is

more useful as a marker of myocardial infarction and hemolysis [18]. (See "Biomarkers

suggesting cardiac injury other than troponins and creatine kinase".)

Glutamate dehydrogenase — Glutamate dehydrogenase, a mitochondrial enzyme, is found

primarily in the liver, heart, muscle and kidneys [20]. In the liver, it is present in highest

concentration in centrilobular hepatocytes [21]. Because of this location, serum glutamate

dehydrogenase has been evaluated as a specific marker for liver disorders such as alcoholic

hepatitis, that primarily affect centrilobular hepatocytes [22]. Although an initial report suggested

that glutamate dehydrogenase may be a sensitive and relatively specific marker for alcoholic

hepatitis, this observation has not been confirmed by others [1,23]. Measurement of serum

glutamate dehydrogenase is seldom performed.

Isocitrate dehydrogenase — Isocitrate dehydrogenase, a cytoplasmic enzyme, is found in the

liver, heart, kidneys, and skeletal muscle [24]. Its activity in serum parallels that of the serum

aminotransferases in acute and chronic hepatitis, but it is less sensitive [25,26]. Although

elevations in serum isocitrate dehydrogenase are relatively specific for liver disorders, increased

concentrations have been reported in disseminated malignancy without detectable hepatic

involvement [27]. Measurement of this enzyme offers no diagnostic advantage over the serum

aminotransferases.

Sorbitol dehydrogenase — Sorbitol dehydrogenase is a cytoplasmic enzyme found

predominantly in the liver with relatively low concentrations in the prostate gland and kidneys

[24]. Its activity in serum parallels that of the aminotransferases in hepatobiliary disorders.

However, it appears to be less sensitive, and values may be normal in cirrhosis and other

chronic liver disorders. Its instability in serum further limits its diagnostic usefulness [24].

SUMMARY AND RECOMMENDATIONS

●A number of blood tests are available that reflect the condition of the liver. The most

common tests used in clinical practice include the serum aminotransferases, bilirubin,

alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as

"liver function tests", although this term is somewhat misleading since most do not

accurately reflect how well the liver is functioning, and abnormal values can be caused by

diseases unrelated to the liver. In addition, these tests may be normal in patients who have

advanced liver disease. (See "Approach to the patient with abnormal liver biochemical and

function tests".)

●The serum aminotransferases (formerly called transaminases) are sensitive indicators of

hepatocyte injury. The most commonly measured are alanine aminotransferase (ALT,

serum glutamic-pyruvic transaminase [SGPT]) and aspartate aminotransferase (AST,

serum glutamic-oxaloacetic transaminase [SGOT]). (See 'Serum

aminotransferases'above.)

●Serum aminotransferases are elevated in most liver diseases and in disorders that

involve the liver (such as various infections, acute and chronic heart failure, and metastatic

carcinoma). Elevations up to eight times the upper limit of normal are nonspecific and may

be found in any of the above disorders. The highest elevations occur in disorders

associated with extensive hepatocellular injury, such as acute viral hepatitis, ischemic

hepatitis (shock liver), and acute drug- or toxin-induced liver injury

(eg, acetaminophentoxicity). (See 'Serum aminotransferases' above.)

●A variety of other hepatic enzymes (such as lactate dehydrogenase) have been

measured, but none is as useful as the aminotransferases for the diagnosis of hepatic

disease. (See 'Serum concentrations of other hepatic enzymes' above.)Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)AuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jan 21, 2015.

INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.

The most common tests used in clinical practice include the serum aminotransferases, bilirubin,

alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver

function tests," although this term is somewhat misleading since most do not accurately reflect

how well the liver is functioning, and abnormal values can be caused by diseases unrelated to

the liver. In addition, these tests may be normal in patients who have advanced liver disease.

Several specialized tests have also been developed (such as indocyanine green [ICG]

clearance), which, although uncommonly used in clinical practice, can measure specific aspects

of hepatic function.

Despite their limitations, liver biochemical and function tests have many applications in clinical

medicine:

●They provide a noninvasive method to screen for the presence of liver disease. The

serum aminotransferases, for example, are part of a panel of tests used to screen all blood

donors in the United States for the presence of transmissible viruses.

●They can be used to measure the efficacy of treatments for liver disease (such as

immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:

Treatment".)

●They can be used to monitor the progression of a disease such as viral or alcoholic

hepatitis.

●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.

As an example, the Child-Turcotte-Pugh score (Child-Pugh class), which incorporates the

prothrombin time and serum bilirubin and albumin concentrations, can predict survival

(table 1). Similarly, the Model for End-stage Liver Disease (MELD) score, based in part

upon the serum bilirubin, is an accurate predictor of three-month mortality and is used

routinely in determining the priority of patients awaiting liver transplantation. (See "Model

for End-stage Liver Disease (MELD)".)

The pattern of abnormalities on these tests is more accurate than any of the individual tests. An

elevation of serum aminotransferases indicates hepatocellular injury, while an elevation of

alkaline phosphatase indicates cholestasis. Recognizing patterns that are consistent with

specific diseases can prompt appropriate additional testing.

The liver biochemical and function tests that are used commonly in clinical practice and that are

used occasionally for specific circumstances can be categorized as follows:

●Tests that detect injury to hepatocytes – Most of these tests measure the concentration

of hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are

normally intracellular but are released when hepatocytes are injured. (See "Liver

biochemical tests that detect injury to hepatocytes".)

●Tests of the liver's capacity to transport organic anions and metabolize drugs – These

tests measure the liver's ability to clear endogenous or exogenous substances from the

circulation. The best studies include serum measurements of bilirubin, bile acids, caffeine,

and lidocaine metabolites, a variety of breath tests, and clearance tests such as

bromsulphalein (BSP) and ICG.

●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess

the biosynthetic capacity of the liver are the serum albumin and the prothrombin time

(which requires the presence of clotting factors produced in the liver). Other tests that have

been used are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and alpha-

1 antitrypsin.

●Tests that detect chronic inflammation in the liver, altered immunoregulation, or viral

hepatitis — These tests include the immunoglobulins, hepatitis serologies, and specific

autoantibodies. Most of these substances are proteins made by B lymphocytes, not by

hepatocytes. However, some are quite specific for certain liver diseases, such as

antimitochondrial antibodies in primary biliary cirrhosis. (See "Clinical manifestations,

diagnosis, and prognosis of primary biliary cirrhosis".)

The liver contains thousands of enzymes, some of which are also present in serum in very low

concentrations. Elevation of an enzyme activity in the serum primarily reflects release from

damaged liver cells. Elevation of serum enzyme tests can be grouped into two categories:

●Enzymes that reflect generalized damage to hepatocytes

●Enzymes that reflect cholestasis

This topic review will discuss the serum tests that reflect cholestasis. The other categories of

liver function tests and enzymes that reflect generalized damage to hepatocytes are discussed

separately. (See "Liver biochemical tests that detect injury to hepatocytes".)

ALKALINE PHOSPHATASE — Alkaline phosphatase refers to a group of enzymes that

catalyze the hydrolysis of a large number of organic phosphate esters at an alkaline pH

optimum. Although alkaline phosphatase is found in many locations throughout the body, its

precise function is not yet known [1]. It appears to have an active role in down-regulating the

secretory activities of the intrahepatic biliary epithelium [2], detoxifying lipopolysaccharide, and

hydrolyzing phosphate esters to generate inorganic phosphate for uptake by various tissues [3].

In bone, the enzyme is involved with calcification. At other sites, it may participate in transport

processes.

At least three separate genes code for the different alkaline phosphatases that exist in multiple

isoenzyme forms [4]. Most of the alkaline phosphatase isoenzymes of clinical interest are

derived from the liver, bone, first trimester placenta, and kidneys, and are coded for by one

gene. They are called tissue unspecific alkaline phosphatase since they have the same

immunologic properties and amino acid sequence. Although these alkaline phosphatase

isoenzymes catalyze the same reactions, they have different physicochemical properties, which

are conferred by carbohydrate and lipid side chains added during posttranslational modification

[1].

A second alkaline phosphatase gene codes for third trimester placental and intestinal alkaline

phosphatase [4]. The third gene codes for a second type of intestinal alkaline phosphatase.

Alkaline phosphatase activity in serum is derived primarily from three sources: liver, bone, and

in some patients the intestinal tract [1,5]. The intestinal contribution (about 10 to 20 percent) is

of importance primarily in people with blood groups O and B who are secretors of the ABH red

blood cell antigen [6]; it is enhanced by consumption of a fatty meal [7,8] and has limited clinical

importance.

Circulating alkaline phosphatase appears to behave like other serum proteins [9]. Its half-life is

seven days, and its clearance from serum is independent of the functional capacity of the liver

or the patency of the bile ducts [9]. Its sites of degradation are unknown.

Mechanism of elevated concentration in hepatobiliary disorders — Increased serum

alkaline phosphatase is derived from tissues whose metabolism is either functionally disturbed

(the obstructed liver) or greatly stimulated (placenta in the third trimester of pregnancy and bone

in growing children). Although the cause of elevated serum alkaline phosphatase levels is

understood in patients with increased bone or placental isoenzymes, the cause in hepatobiliary

disease has been debated [10]. Two theories were proposed in the past: the damaged liver

regurgitates hepatic alkaline phosphatase back into serum; and the damaged liver, particularly if

due to obstructive jaundice, fails to excrete the alkaline phosphatase made in bone, the

intestines, and the liver.

This long-standing debate has been resolved in favor of the regurgitation of liver alkaline

phosphatase into serum. The data supporting this theory are compelling:

●Only hepatic alkaline phosphatase is found in the serum of patients with liver disease,

particularly cholestasis [11].

●The clearance rates of infused placental alkaline phosphatase are the same in patients

with bile duct obstruction and healthy controls [9].

●In experimental bile duct obstruction in rats, the entire increase in serum alkaline

phosphatase activity is due to the leakage of hepatic alkaline phosphatase into serum [12].

The increased serum activity is paralleled by a striking elevation in hepatic alkaline

phosphatase activity and is not accounted for by biliary retention of alkaline phosphatase.

Thus, the elevation in serum alkaline phosphatase in hepatobiliary disease results from

increased de novo synthesis in the liver followed by release into the circulation [13]. Retained

bile acids appear to play a central role in this process; they induce the synthesis of the enzyme

and may cause it to leak into the circulation, perhaps by disruption of hepatic organelles and

solubilization of phosphatase bound to such membranes [14].

The precise manner in which the alkaline phosphatase reaches the circulation is unclear. In

some patients with cholestasis, small vesicles that contain many basolateral (sinusoidal)

membrane enzymes still bound to these membranes, including alkaline phosphatase, have

been found in serum [15].

Measurement — The most widely used procedure for determination of serum alkaline

phosphatase activity involves measuring the release of p-nitrophenol or phosphate from p-

nitrophenylphosphate under specified conditions. The results are expressed in international

units (IU/L), which is the activity of alkaline phosphatase that releases 1 mmol of chromogen or

Pi per minute.

Alkaline phosphatase isoenzymes can be determined using a variety of techniques. Although

the isoenzymes can be separated by electrophoresis, bone and liver isoenzymes differ only

slightly in electrophoretic mobility and often overlap if run on the electrophoretic systems used in

most clinical laboratories. Separation using polyacrylamide gel slabs is the most reliable method

and produces clear-cut separations of the liver, bone, intestinal, and placental isoenzymes.

However, this method is not always available. Electrophoresis on cellulose acetate, with the

addition of heat inactivation, may accomplish the same purpose [16].

A second method is based upon the observation that alkaline phosphatases from individual

tissues differ in their susceptibility to inactivation by heat or 2 mol urea [17]. Placental alkaline

phosphatase and an isoenzyme found in certain cancers, the Regan isoenzyme, are fully heat-

stable after exposure to a temperature of 56°C for 15 minutes [18]. Thus, the finding of an

elevated serum alkaline phosphatase concentration in a patient in whom all the excess activity

is in a heat-stable fraction strongly suggests that the placenta or a tumor is the source of the

elevated enzyme in serum. Unfortunately, in nonselected patients, this method has many

limitations and is not recommended.

Because none of these methods is widely available, the most practical approach is to measure

other enzymes whose elevation reflects liver disease. These include 5'- nucleotidase and

gamma-glutamyl transpeptidase. (See '5'-Nucleotidase' below and 'Gamma-glutamyl

transpeptidase' below.)

Clinical significance — The major value of the serum alkaline phosphatase in the diagnosis of

liver disorders is in the recognition of cholestatic disease (table 2) [19]. However, an elevation in

the alkaline phosphatase concentration is a relatively common finding and does not always

indicate the presence of hepatobiliary disease (algorithm 1). In addition, normal serum values of

alkaline phosphatase vary based upon demographic and clinical circumstances:

●In the 15- to 50-year age group, mean serum alkaline phosphatase activity is somewhat

higher in men than in women [20]. In comparison, in individuals over age 60, the enzyme

activity of women equals or exceeds that of men [21].

●In children, serum alkaline phosphatase activity is considerably elevated in both sexes,

correlates well with the rate of bone growth, and appears to be accounted for by the influx

of enzymes from osteoid tissue [20,22]. Serum alkaline phosphatase in normal adolescent

males may reach mean values three times greater than in normal adults without implying

the presence of hepatobiliary disease (figure 1) [20,23]. Infants and young children

occasionally display marked transient elevation of serum alkaline phosphatase activity in

the absence of detectable liver or bone disease. (See "Transient hyperphosphatasemia of

infancy and early childhood".)

●Patients older than 60 have somewhat higher values (up to 1.5 times normal) than

younger adults [21,24]. The alkaline phosphatase is usually derived from the liver in older

men and from bone in postmenopausal women [21].

●Enzyme activity in serum may double late in normal pregnancy, primarily because of an

influx from the placenta [25].

Identifying the source of the elevated isoenzyme is helpful if an elevated serum alkaline

phosphatase is the only abnormal finding in an apparently healthy person or if the degree of

elevation is higher than expected in the clinical setting. One series evaluated 317 patients in a

university hospital who were evaluated for an increased serum alkaline phosphatase level: the

source of elevation was the liver and bone in 80 and 18 percent, respectively [11]. The

remaining patients had either a mixed or an intestinal source.

If alkaline phosphatase fractionation is not available, differentiation of the source of elevation

can also be accomplished by obtaining additional enzyme tests. The best studied are the serum

5'-nucleotidase and gammaglutamyl transpeptidase (GGT) concentrations (see below); one or

the other can be obtained to evaluate an elevated alkaline phosphatase. An older test, leucine

aminopeptidase, is now rarely used. These enzyme tests are not elevated in bone disorders,

and leucine aminopeptidase and possibly 5'-nucleotidase are not elevated in pregnancy.

Thus, an increased serum concentration of these enzymes in nonpregnant patients indicates

that an elevated serum alkaline phosphatase is due at least in part to hepatobiliary disease.

However, a lack of increased serum 5'-nucleotidase in the presence of an elevated alkaline

phosphatase level does not exclude liver disease because these enzymes do not necessarily

increase in a parallel manner in early or modest hepatic injury [26]. (See "Approach to the

patient with abnormal liver biochemical and function tests".)

Marked elevation — Approximately 75 percent of patients with prolonged cholestasis have

serum alkaline phosphatase values increased to four times the upper limit of normal or more.

Elevations of this magnitude can occur in a variety of diseases associated with extrahepatic or

intrahepatic obstruction (table 2), and the extent of the elevation does not distinguish between

the two:

●Obstructive jaundice due to cancer

●Bile duct stones

●Sclerosing cholangitis (primary or secondary)

●Bile duct stricture

●Drug and toxins associated with cholestasis

●Primary biliary cirrhosis

●Liver allograft rejection

●Infectious hepatobiliary diseases seen in patients with AIDS (eg, cytomegalovirus or

microsporidiosis and tuberculosis with hepatic involvement)

●Infiltrative liver disease (eg, sarcoidosis, tuberculosis, metastatic malignancy,

amyloidosis)

●Alcoholic hepatitis (rarely) [27]

Moderate elevation — Lesser increases in alkaline phosphates activity, up to four times the

upper limit of normal, are nonspecific and occur in all types of liver disease, including viral

hepatitis, chronic hepatitis, cirrhosis, infiltrative diseases of the liver, and congestive heart failure

(table 2) [8,10,28]. Elevations in hepatic alkaline phosphatase of this magnitude can also occur

in disorders that do not directly involve the liver, such as Hodgkin lymphoma, myeloid

metaplasia, intra-abdominal infections, and osteomyelitis [11].

A two- to fourfold elevation in serum alkaline phosphatase levels has been described in several

members of a family who had no evidence of bone or liver disease [29]. The elevation appeared

to be transmitted as an autosomal dominant trait, but the site of the excess alkaline

phosphatase could not be determined.

Isolated or disproportionate elevation — Isolated elevations of hepatic alkaline phosphatase

or disproportionate elevation compared with other tests, such as the serum aminotransferases

and bilirubin, can occur in a number of circumstances including:

●Partial bile duct obstruction due to gallstones or tumor. The mechanism is unknown but

probably represents local areas of bile duct obstruction with induced synthesis of hepatic

alkaline phosphatase and leakage of the alkaline phosphatase into the serum.

●Early in the course of some cholestatic liver diseases such as primary sclerosing

cholangitis and primary biliary cirrhosis.

●Infiltrative diseases such as amyloidosis, sarcoidosis, hepatic abscesses, tuberculosis,

and metastatic carcinoma.

●Ischemic cholangiopathy.

●Extrahepatic diseases such as myeloid metaplasia, peritonitis, diabetes mellitus,

subacute thyroiditis, uncomplicated gastric ulcer, and sepsis. The increase in alkaline

phosphatase in these disorders is thought to be related to hepatic dysfunction despite the

absence of overt liver disease [30].

●Extrahepatic tumors, including osteosarcomas; lung, gastric, head and neck, renal cell,

ovarian, and uterine cancers; and Hodgkin lymphoma, that secrete alkaline phosphatase

(often a form known as the Regan isoenzyme) or cause leakage of hepatic alkaline

phosphatase into serum by an unknown mechanism [11,31].

●Certain drugs such as phenytoin.

●Infants and young children occasionally display marked transient elevation of serum

alkaline phosphatase activity in the absence of detectable liver or bone disease. The

hyperphosphatasemia typically includes elevations in both bone and liver isoenzymes, and

appears to be caused by delayed clearance of the enzyme. The clinical presentation and

evaluation of an infant or child with this finding is discussed separately. (See "Transient

hyperphosphatasemia of infancy and early childhood".)

Subnormal values — Extremely low serum alkaline phosphatase concentrations can be seen

in patients with fulminant Wilson disease complicated by hemolysis [32,33]. (See"Wilson

disease: Diagnostic tests".)

Low values can also occur in patients with hypothyroidism, pernicious anemia, zinc deficiency,

congenital hypophosphatemia, and certain types of progressive familial intrahepatic cholestasis

in children.

Non-hepatic alkaline phosphatase — As noted above, bone is the most likely source of

isolated plasma alkaline phosphatase that is not of liver origin (in nonpregnant patients). An

elevated bone alkaline phosphatase is indicative of high bone turnover, which may be caused

by several disorders including healing fractures, osteomalacia, hyperparathyroidism,

hyperthyroidism, Paget disease of bone, osteogenic sarcoma, and bone metastases. If the

etiology is unclear, referral to an endocrinologist for evaluation is often the next step. Initial

testing may include measurement of serum calcium, parathyroid hormone, 25-hydroxy vitamin

D, and imaging with bone scintigraphy. (See "Bone physiology and biochemical markers of

bone turnover", section on 'Markers of bone turnover' and "Clinical manifestations and diagnosis

of Paget disease of bone", section on 'Clinical manifestations' and "Clinical manifestations,

diagnosis, and treatment of osteomalacia", section on 'Diagnosis and evaluation'.)

Intestinal alkaline phosphatase has multiple biological functions [3,34]. As noted above,

elevated levels in serum are usually of no clinical importance. They are most often found

postprandially after a fatty meal and tend to run in families, suggesting that there may be a

genetic basis [35]. Because elevation is nonspecific, it should not prompt evaluation for a

particular intestinal disorder. Normalization of the level while fasting can help reassure that its

origin is intestinal.

5'-NUCLEOTIDASE — 5'-Nucleotidase is found in the liver, intestine, brain, heart, blood

vessels, and endocrine pancreas [36]. Although its physiologic function is unknown, 5'-

nucleotidase specifically catalyzes hydrolysis of nucleotides such as adenosine 5'-phosphate

and inosine 5'-phosphate, in which the phosphate is attached to the 5 position of the pentose

moiety.

Similar to alkaline phosphatase, 5'-nucleotidase has a subcellular location in hepatocytes [37]. It

is bound to bile canalicular and sinusoidal membranes [38] and must be solubilized, perhaps via

the detergent action of bile acids, to gain access to the circulation. In experimental bile duct

obstruction in rats, bile acid concentrations rapidly reach levels sufficient to disrupt plasma

membranes and solubilize the enzyme [39]. The same phenomenon may occur in hepatobiliary

disorders in which there is any degree of cholestasis [37].

Measurement — Serum 5'-nucleotidase activity is most commonly assayed by measuring the

release of inorganic phosphate using 5'-phosphate as a substrate [40]. A unit of 5'-nucleotidase

activity is designated as equivalent to that amount of enzyme that liberates 1 mg of phosphate

per 100 mL of serum per hour (1 mg/dL per hour). These units are analogous to the old

Bodansky units of alkaline phosphatase activity [41]. The presence of alkaline phosphatase in

serum complicates the assay because it also hydrolyzes the 5'-nucleotide substrates, and

corrections must be made for its activity.

In most series of normal adults, the serum 5'-nucleotidase concentration ranges from 0.3 to 3.2

Bodansky units and is not clearly influenced by gender or race [42,43]. Values are substantially

lower in children than in adults, rise gradually in adolescence, and reach a plateau after age 50

[44].

Clinical significance — Elevations in serum 5'-nucleotidase are seen in the same types of

hepatobiliary diseases associated with an increased serum alkaline phosphatase. Most studies

suggest that serum alkaline phosphatase and 5'-nucleotidase are equally valuable in

demonstrating biliary obstruction or hepatic infiltrative and space-occupying lesions [43,45].

Although values of the two enzymes are generally correlated, the concentrations may not rise

proportionately in individual patients [42,46]. Thus, in selected patients, one enzyme may be

elevated and the other normal.

Conflicting data have been reported for serum 5'-nucleotidase activity during normal pregnancy

[47,48]. In contrast, most studies show that serum 5'-nucleotidase does not rise in bone

disease, [49] and in the few instances in which an increase was observed, it was of low

magnitude [46].

Thus, the major value of the 5'-nucleotidase assay is its specificity for hepatobiliary disease. An

increased serum 5'-nucleotidase concentration in a nonpregnant person suggests that a

concomitantly increased serum alkaline phosphatase is of hepatic origin. However, because of

the occasional dissociation between the two enzymes, a normal serum 5'-nucleotidase does not

rule out the liver as the source of an elevated serum alkaline phosphatase.

GAMMA-GLUTAMYL TRANSPEPTIDASE — Gamma-glutamyl transpeptidase (GGT)

catalyzes the transfer of the gamma-glutamyl group from gamma-glutamyl peptides such as

glutathione to other peptides and to L-amino acids. GGT is present in cell membranes in many

tissues, including the kidneys, pancreas, liver, spleen, heart, brain, and seminal vesicles [50]. It

is thought to play a role in amino acid transport [51].

Measurement — Enzyme activity is most commonly assayed using gamma-L-glutamyl-r-

nitroanilide as a substrate [52]. The liberated product, (chromogen r-nitroaniline) can be

measured spectrophotometrically.

Clinical significance — GGT is present in the serum of healthy individuals. The normal range

is 0 to 30 IU/L (0 to 0.5 mkat/L). Most studies have found values to be comparable in men and

women [53,54], although some reports have noted higher values in men [55]. Newborn infants

have serum GGT activity six to seven times the upper limit of the adult reference range; levels

decline and reach adult levels by five to seven months of age [56]. Serum enzyme activity does

not rise during the course of normal pregnancy [54].

Elevated serum activity is found in diseases of the liver, biliary tract, and pancreas, and reflects

the same spectrum of hepatobiliary disease as alkaline phosphatase, 5'-nucleotidase, and

leucine aminopeptidase. Serum GGT and alkaline phosphatase correlate reasonably well.

There are conflicting data as to whether serum GGT has better sensitivity for hepatobiliary

disease than alkaline phosphatase or leucine aminopeptidase [54,57].

As with serum 5'-nucleotidase, the major clinical value of serum GGT is in conferring organ

specificity to an elevated value for alkaline phosphatase since GGT activity is not increased in

patients with bone disease [54]. However, an elevation in serum GGT is not completely specific

for hepatobiliary disease. High serum GGT values are found in people who take medicines such

as barbiturates or phenytoin [58] or ingest large quantities of alcohol [59] even when values for

other serum enzyme tests and serum bilirubin are normal. In these settings, there is no

correlation between the serum GGT and alkaline phosphatase [50].

An isolated elevation in serum GGT or a GGT elevation out of proportion to that of other

enzymes (such as the alkaline phosphatase and alanine aminotransferase) may be an indicator

of alcohol abuse or alcoholic liver disease [60]. The reasons for this are not well understood.

Although hepatic microsomal GGT may be induced by alcohol [61], neither elevated serum GGT

nor a history or recent alcohol ingestion correlates with hepatic GGT activity in patients with

biopsy-proven alcoholic liver disease [62,63]. In vitro studies suggest an alternative mechanism:

alcohol may cause the leakage of GGT from hepatocytes [61].

Aside from its value in conferring liver specificity to an elevated serum alkaline phosphatase

level and its possible use in identifying patients with alcohol abuse, serum GGT offers no

advantage over aminotransferases and alkaline phosphatase. In one prospective study that

included 1040 nonselected inpatients, 13 percent had an elevated serum GGT activity; only 32

percent had hepatobiliary disease [64]. In the remaining patients, the elevated serum GGT may

have been due to alcohol ingestion or medications, which caused a temporary rise in levels but

without liver disease.

SUMMARY AND RECOMMENDATIONS

●Alkaline phosphatase refers to a group of enzymes that catalyze the hydrolysis of a large

number of organic phosphate esters at an alkaline pH optimum. Although alkaline

phosphatase is found in many locations throughout the body, its precise function is not yet

known.

●The major value of the serum alkaline phosphatase in the diagnosis of liver disorders is

in the recognition of cholestatic disease (table 2). However, an elevation in the alkaline

phosphatase concentration is a relatively common finding and does not always indicate

the presence of hepatobiliary disease. The degree of elevation does not distinguish

between intra- and extra-hepatic cholestasis (algorithm 1). (See "Approach to the patient

with abnormal liver biochemical and function tests".)

●Elevations in serum 5'-nucleotidase are seen in the same types of hepatobiliary diseases

associated with an increased serum alkaline phosphatase. Most studies suggest that

serum alkaline phosphatase and 5'-nucleotidase are equally valuable in demonstrating

biliary obstruction or hepatic infiltrative and space-occupying lesions.

●Elevated serum levels of gamma-glutamyl transpeptidase are found in diseases of the

liver, biliary tract, and pancreas, and reflect the same spectrum of hepatobiliary disease as

alkaline phosphatase, 5'-nucleotidase, and leucine aminopeptidase. Serum GGT and

alkaline phosphatase correlate reasonably well. There are conflicting data as to whether

serum GGT has better sensitivity for hepatobiliary disease than alkaline phosphatase or

leucine aminopeptidase.Classification and causes of jaundice or asymptomatic hyperbilirubinemiaAuthorsNamita Roy-Chowdhury, PhDJayanta Roy-Chowdhury, MD, MRCPSection EditorsSanjiv Chopra, MD, MACPElizabeth B Rand, MDDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Namita Roy-Chowdhury, PhD Nothing to disclose. Jayanta Roy-Chowdhury, MD, MRCP Nothing to disclose. Sanjiv Chopra, MD, MACP Nothing to disclose. Elizabeth B Rand, MD Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Dec 08, 2014.

INTRODUCTION — The normal serum bilirubin concentration in children and adults is less than

1 mg/dL (17 micromol/liter), less than 5 percent of which is present in conjugated form. The

measurement is usually made using diazo reagents and spectrophotometry. Conjugated

bilirubin reacts rapidly ("directly") with the reagents. The measurement of unconjugated bilirubin

requires the addition of an accelerator compound and is often referred to as the indirect

bilirubin. (See "Clinical aspects of serum bilirubin determination".)

Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical

examination cannot detect jaundice until the serum bilirubin is greater than

2 mg/dL (34micromol/liter), twice the normal upper limit. The yellow discoloration is best seen in

the periphery of the ocular conjunctivae and in the oral mucous membranes (under the tongue,

hard palate). Icterus may be the first or only sign of liver disease; thus its evaluation is of critical

importance.

For clinical purposes, the predominant type of bile pigments in the plasma can be used to

classify hyperbilirubinemia into two major categories (table 1 and algorithm 1A-B).

●Plasma elevation of predominantly unconjugated bilirubin due to the overproduction of

bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation

●Plasma elevation of both unconjugated and conjugated bilirubin due to hepatocellular

diseases, impaired canalicular excretion, and biliary obstruction

In some situations, both overproduction and reduced disposition contribute to the accumulation

of bilirubin in plasma.

The frequency with which the different causes of jaundice occur varies markedly depending

upon multiple factors such as age, geography, and socioeconomic class [1]. The causes of

hyperbilirubinemia presenting in the neonatal period are quite different from those presenting

later in life, and are discussed separately. (See "Pathogenesis and etiology of unconjugated

hyperbilirubinemia in the newborn" and "Causes of neonatal cholestasis".)

This topic will review the causes of jaundice. A schematic depiction of the hepatobiliary

excretion pathway with disorders causing jaundice and their main site of interference with

bilirubin metabolism and excretion is presented in the figure (figure 1). The diagnostic approach

to the patient with jaundice is discussed separately. (See "Diagnostic approach to the adult with

jaundice or asymptomatic hyperbilirubinemia".)

REFERENCE RANGES — Liver test reference ranges will vary from laboratory to laboratory.

As an example, one hospital's normal reference ranges for adults are as follows [2]:

●Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)

●Alkaline phosphatase:

•Male: 45 to 115 int. unit/L

•Female: 30 to 100 int. unit/L

●Alanine aminotransferase (ALT):

•Male: 10 to 55 int. unit/L

•Female: 7 to 30 int. unit/L

●Aspartate aminotransferase (AST):

•Male: 10 to 40 int. unit/L

•Female: 9 to 32 int. unit/L

●Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)

●Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)

●Gamma-glutamyl transpeptidase (GGT):

•Male: 8 to 61 int. unit/L

•Female: 5 to 36 int. unit/L

●Prothrombin time (PT): 11.0 to 13.7 seconds

DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA — Three basic

pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin uptake, and

impaired bilirubin conjugation, are mainly responsible for unconjugated hyperbilirubinemia. The

physiologic jaundice of the neonate represents a classic example which combines all of these

mechanisms.

Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown

of heme derived from hemoglobin (figure 2). Extravascular or intravascular hemolysis,

extravasation of blood in tissues, or dyserythropoiesis are causes of enhanced heme

catabolism. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin

overproduction".)

Extravascular hemolysis — The reticuloendothelial cells of the spleen, bone marrow, and liver

are responsible for the increased extravascular destruction of erythrocytes which occurs in most

hemolytic disorders. These phagocytic mononuclear cells are rich in heme oxygenase and

biliverdin reductase activities and rapidly degrade heme to bilirubin (figure 2). (See "Bilirubin

metabolism".)

Extravasation — When blood is extravasated into tissues, erythrocytes are phagocytosed by

tissue macrophages that degrade heme to biliverdin and subsequently bilirubin, resulting in the

sequential green and yellow discoloration of the skin overlying a hematoma.

Intravascular hemolysis — With intravascular hemolysis, bilirubin is predominantly formed in

the liver and the kidneys. Hemoglobin released in the circulation is bound to haptoglobin; this

complex is internalized and degraded by hepatocytes. However, circulating haptoglobin may be

depleted with massive hemolysis. In these cases, unbound hemoglobin is converted to

methemoglobin, from which heme is transferred to hemopexin or to albumin forming

methemalbumin. Heme-hemopexin and methemalbumin are internalized by hepatocytes, where

heme is degraded to bilirubin.

A significant fraction of free methemoglobin is filtered by renal glomeruli after dissociation of the

tetrameric globin to two dimers. Only the free (unbound) dimer is small enough to be filtered

across the glomeruli. The heme moiety of filtered methemoglobin is largely degraded by tubular

epithelial cells to bilirubin.

Dyserythropoiesis — Dyserythropoiesis is a term used in a variety of diseases including

megaloblastic and sideroblastic anemias, severe iron deficiency anemia, erythropoietic

porphyria, erythroleukemia, lead poisoning, and a rare disorder of unknown pathogenesis

termed primary shunt hyperbilirubinemia [3,4]. In these disorders, the incorporation of

hemoglobin into erythrocytes is defective, leading to the degradation of a large fraction of

unincorporated hemoglobin heme.

Serum bilirubin concentration — In a stress situation, hemolysis, and therefore unconjugated

bilirubin production, can increase up to 10-fold. The canalicular excretion of bilirubin is the rate-

limiting step in bilirubin elimination since hepatic conjugating capacity normally exceeds

maximum bilirubin production. These relationships account for two findings at a steady state of

maximum bilirubin production in patients with normal hepatic function:

●The serum bilirubin concentration will not exceed 4 mg/dL (68 micromol/liter) in patients

with normal liver function [5]; however, hemolysis can lead to severe hyperbilirubinemia in

patients who have even mild hepatic disease.

●The proportion of conjugated bilirubin in plasma (approximately 3 to 5 percent of the

total) remains normal [6].

There are two reasons why the bilirubin concentration increases during hemolysis in the

presence of normal bilirubin glucuronidation. First, bilirubin is produced mainly outside the liver;

as a result, it must enter the blood stream during transit to the liver. Second, a small amount of

bilirubin taken up by the hepatocyte is transferred to plasma by diffusion or via ATP-consuming

mechanisms. Because conjugated bilirubin is very efficiently cleared, the proportion of

conjugated bilirubin in the plasma (around 5 percent) does not increase until canalicular

excretion capacity is exceeded. At that point, a disproportionate amount of conjugated bilirubin

accumulates.

Bilirubin overproduction with coexisting liver disease — Most liver diseases affect

canalicular excretion, resulting in the accumulation of both conjugated and unconjugated

bilirubin in hepatocytes. In cholestatic states, the canalicular ATP-dependent organic anion

pump, MRP2, is down-regulated. This may lead to upregulation of other forms of MRP, such as

MRP3, in the contiguous membranes of the hepatocyte, resulting in active transport of

unconjugated and conjugated bilirubin into the plasma [7,8]. Thus, plasma bilirubin

accumulating in conditions resulting from a combination of bilirubin overload and liver disease is

always a mixture of unconjugated and conjugated bilirubin. In cases where there is an inherited

deficiency of conjugation (eg, Gilbert syndrome), hemolysis causes almost pure unconjugated

hyperbilirubinemia. The rate-limiting step in these patients is bilirubin glucuronidation, rather

than canalicular excretion. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to

bilirubin overproduction".)

Serum bilirubin level is of particular significance when diagnosing Wilson disease in the setting

of acute liver failure. In contrast to most liver diseases, serum alkaline phosphatase activity is

low or normal in Wilson disease and, because of bilirubin overproduction due to hemolysis, the

serum bilirubin level is high. A serum alkaline phosphatase (int.unit/L)/bilirubin (mg/dl) ratio of

<4 provides 94 percent sensitivity and 96 percent specificity for the diagnosis of Wilson disease

in adult patients presenting with acute liver failure [9]. However, the sensitivity of this ratio may

be reduced in children, probably because of a higher contribution of alkaline phosphatase from

non-hepatic sources [10]. (See "Wilson disease: Clinical manifestations, diagnosis, and natural

history", section on 'Acute hepatitis and acute liver failure'.)

Urobilinogen excretion — As bilirubin excretion in bile increases in states of bilirubin

overproduction, more urobilinogen appears in the stool and urine. However, the amount of

urobilinogen in stool and urine is not proportional to bilirubin excretion since conversion of

bilirubin to urobilinogen is not quantitative [11].

Gallstones — Chronically increased biliary bilirubin excretion can lead to brown or black

pigment stones consisting of precipitated monoconjugated and unconjugated bile pigments.

Black pigment stones generally form in the gallbladder and may contain polymerized bile

pigments. Brown stones form in the bile ducts, often in the presence of infection. They consist of

calcium bilirubinate, mucin glycoproteins, and various other salts.

Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders of

internalization of bilirubin by the hepatocyte result in reduced hepatic bilirubin uptake (figure 3).

Congestive heart failure or portosystemic shunts (spontaneously occurring collaterals in

cirrhosis or surgical shunts) reduce hepatic blood flow and the delivery of bilirubin to

hepatocytes, resulting in predominantly unconjugated hyperbilirubinemia. In some patients with

cirrhosis, the direct contact of plasma with the hepatocytes may be compromised due to

capillarization of the sinusoidal endothelial cells (loss of fenestrae), resulting in a further

reduction in bilirubin uptake [12].

Other causes of abnormal bilirubin uptake include Gilbert syndrome, in which uptake of bilirubin

at the sinusoidal surface of hepatocytes is impaired (see "Gilbert syndrome and unconjugated

hyperbilirubinemia due to bilirubin overproduction"), and the administration of several drugs (eg,

rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a cholecystographic agent).

The drug-induced defect usually resolves within 48 hours after discontinuation of the drug [13].

Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or

absent UDP-glucuronosyltransferase activity is found both in several acquired conditions and

inherited diseases, such as Crigler-Najjar syndrome, type I and II and Gilbert syndrome.

(See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin

overproduction" and "Crigler-Najjar syndrome".) Bilirubin conjugating activity is also very low in

the neonatal liver.

UGT activity toward bilirubin is modulated by various hormones. Hyperthyroidism and ethinyl

estradiol, but not other oral contraceptives, inhibit bilirubin glucuronidation [14]. In comparison,

the combination of progestational and estrogenic steroids results in increased enzyme activity.

Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin

or gentamicin at serum concentrations exceeding therapeutic levels) and by chronic persistent

hepatitis, advanced cirrhosis, and Wilson's disease.

DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA — A variety of

acquired disorders with conjugated hyperbilirubinemia can be categorized according to their

histopathology and pathophysiology: biliary obstruction (extrahepatic cholestasis), intrahepatic

cholestasis, and hepatocellular injury. The differential diagnosis of extrahepatic and intrahepatic

hyperbilirubinemia is summarized in the tables (table 2 and table 3).

Biliary obstruction — In biliary obstruction, both conjugated and unconjugated bilirubin

accumulate in serum. Bilirubin may be transported back to the plasma via an MRP group of

ATP-consuming pumps [8,15]. The serum concentrations of conjugated bilirubin and alkaline

phosphatase can be used as markers for hepatobiliary obstruction. The diagnosis can usually

be established with the help of noninvasive and invasive imaging techniques. (See "Diagnostic

approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)

Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes, where

reversal of glucuronidation may take place. The unconjugated bilirubin formed by this process

may diffuse or be transported back into the plasma.

The differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction is age

dependent. In adults, it includes cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing

cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and chronic

pancreatitis, and strictures after invasive procedures. In children, choledochal cysts and

cholelithiasis are most common. Extrinsic compression from tumors or other anomalies are

seen in all pediatric age groups as well as in adults. In neonates and young infants, important

obstructive processes include biliary atresia and choledochal cysts. (See "Causes of neonatal

cholestasis".)

●In the Mirizzi syndrome, a distended gallbladder caused by an impacted cystic duct stone

may lead to compression of the extrahepatic bile ducts. (See "Mirizzi syndrome".)

●The intrahepatic and extrahepatic portions of the bile ducts can be affected in both PSC

and cholangiocarcinoma. (See "Clinical manifestations and diagnosis of

cholangiocarcinoma".)

●Different parasitic infections can be the cause of biliary obstruction. Adult Ascaris

lumbricoides can migrate from the intestine up the bile ducts, thereby obstructing the

extrahepatic bile ducts. Eggs of certain liver flukes (eg, Clonorchis sinensis, Fasciola

hepatica) can obstruct the smaller bile ducts, resulting in intrahepatic cholestasis.

●AIDS cholangiopathy can be caused by Cryptosporidium sp, cytomegalovirus, or HIV

itself [16]; imaging studies show similar findings to PSC [17] (see "AIDS cholangiopathy").

Only biopsies and bile cultures are able to give a definitive diagnosis.

Establishing the cause of jaundice in patients with AIDS is particularly complex because of its

broad differential diagnosis. It includes viral hepatitis (hepatitis viruses, herpes simplex virus,

Epstein-Barr virus), Mycobacterium tuberculosis and atypical mycobacteria (especially

Mycobacterium avium intracellulare), fungal infections (Cryptococcus neoformans,Histoplasma

capsulatum, Candida albicans, Coccidioides immitis), parasites (Pneumocystis carinii), tumor

infiltration (lymphoma, Kaposi sarcoma), and drug-induced liver disease.

Intrahepatic causes — A number of intrahepatic disorders can lead to jaundice and an

elevated serum alkaline phosphatase (in relation to serum aminotransferases). This

presentation mimics that of biliary obstruction but the bile ducts are patent.

Viral hepatitis — Viral hepatitis can present as a predominantly cholestatic syndrome with

marked pruritus. Unless the patient has risk factors for viral hepatitis, it is difficult to distinguish

this clinically from other causes of cholestasis.

Alcoholic hepatitis — Cholestasis with fever and leukocytosis is often the distinctive sign of

alcoholic hepatitis [18]. The diagnosis should be strongly considered in the jaundiced patient

with ethanol dependency, especially if the ratio of serum AST to ALT exceeds 2.0 with the

values being below 500 int. unit/L. (See "Clinical manifestations and diagnosis of alcoholic fatty

liver disease and alcoholic cirrhosis".)

Nonalcoholic steatohepatitis — Nonalcoholic steatohepatitis has features similar to alcoholic

hepatitis both in terms of histology and signs of cholestasis [19]. A variety of conditions such as

diabetes mellitus, morbid obesity, certain stomach and small bowel operations, and drugs can

cause this disorder. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty

liver disease in adults".)

Primary biliary cirrhosis — Primary biliary cirrhosis typically presents with a cholestatic

picture, though evidence of hepatocellular injury also exists. (See "Clinical manifestations,

diagnosis, and prognosis of primary biliary cirrhosis".)

Drugs and toxins — Drug-induced cholestasis can occur in a dose-related fashion (eg,

alkylated steroids such as methyltestosterone and ethinyl estradiol) or as an idiosyncratic or

allergic reaction in a minority of subjects (eg, chlorpromazine, halothane). Drugs and toxins

causing hepatocellular injury may eventually present as a predominantly cholestatic syndrome

[20]. Therefore, it is imperative in every patient with cholestasis to scrupulously elucidate the

current and past medication history including prescribed and over-the-counter drugs.

Certain plants used in "natural" medicines (eg, Jamaican bush tea) contain pyrrolizidine

alkaloids which may cause veno-occlusive disease of the liver [21,22] (see "Hepatotoxicity due

to herbal medications and dietary supplements"). The outbreak of jaundice that occurred in 84

individuals after accidental methylene dianiline ingestion in England in 1965 has been termed

Epping jaundice [23].

Arsenic, which was used for the treatment of syphilis during the early years of the twentieth

century, also can cause cholestasis. It has recently gained increased attention because of its

contamination of ground water in various parts of the world including West Bengal, India [24],

the southern United States, and Taiwan. In addition to the well-known skin lesions, arsenic-

contaminated drinking water has been associated with hepatic fibrosis and portal hypertension,

usually without the formation of cirrhotic nodules.

Sepsis and low perfusion states — Bacterial sepsis is very often accompanied by cholestasis.

Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the

jaundice in these patients [25-27]. On the other hand, hyperbilirubinemia can promote bacterial

sepsis by increasing intestinal wall permeability and altering mucosal immunity [28]. Signs of

cholestasis can also be found in other low perfusion states of the liver (heart failure,

hypotension) and hypoxemia that is not profound enough to produce hepatic necrosis.

Malignancy — Paraneoplastic syndromes associated with malignancy can induce a reversible

form of cholestasis (Stauffer syndrome) [29]. It has most commonly been described in

association with renal cell carcinoma, though it has also been reported in patients with

malignant lymphoproliferative diseases, gynecologic malignancies, and prostate cancer [30,31].

(See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)

Liver infiltration — Infiltrative processes of the liver (eg, amyloidosis, lymphoma, sarcoidosis,

tuberculosis) can precipitate intrahepatic cholestasis.

Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited diseases

such as Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic

cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and low phospholipid-

associated cholelithiasis (LPAC). BRIC is seen in adolescents and adults, while LPAC presents

mainly in young adults. (See "Inherited disorders associated with conjugated

hyperbilirubinemia".)

Disorders of fatty acid oxidation are characterized by episodes of metabolic decompensation,

with hypoglycemia, liver dysfunction, and/or cardiomyopathy, triggered by fasting or intercurrent

illness. These disorders may present at any age, from birth through adulthood. (See "Metabolic

myopathies caused by disorders of lipid and purine metabolism", section on 'Defects of beta-

oxidation enzymes'.)

Inherited diseases that cause conjugated hyperbilirubinemia that present during the neonatal

period include Alagille syndrome, cystic fibrosis, and disorders of carbohydrate, lipid, or bile acid

metabolism. (See "Causes of neonatal cholestasis".)

Total parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in

patients receiving total parenteral nutrition (TPN). This complication usually requires at least two

to three weeks of therapy for the development of cholestasis [32]. The underlying illness,

preexisting liver disease, hepatotoxic drugs, and the TPN itself all may contribute to the

cholestasis.

TPN promotes bacterial overgrowth in the small intestine, which in turn favors conditions well

known to induce cholestasis such as translocation of intestinal endotoxins into the portal system

[33], bacterial sepsis [34], and the formation of secondary bile acids (eg, lithocholic acid)

(see "Management of the short bowel syndrome in adults"). Other contributing factors to

cholestasis include biliary sludge, which occurs in all patients after six weeks of TPN, and

hepatotoxic factors such as tryptophan degradation products and aluminum contaminants.

Infants are particularly prone to TPN cholestasis, particularly those born prematurely.

Contributing factors and potential treatment approaches are discussed separately.

(See "Causes of neonatal cholestasis", section on 'Intestinal failure-associated liver disease'.)

Postoperative patient — Jaundice occurs regularly in postoperative patients and is usually

multifactorial in origin. Serum unconjugated bilirubin levels may increase because of blood

transfusions, hematoma resorption, and hemolysis after heart surgery. Other contributing

factors include sepsis, TPN, the administration of hepatotoxic drugs during surgery (such as

halothane) [35], postoperative hypoxia, hypotension, or a newly acquired viral hepatitis [36].

Concomitant renal failure will exaggerate the hyperbilirubinemia. (See "Approach to the patient

with postoperative jaundice".)

Surgery also can exacerbate a preexisting hemolytic disease or unmask an underlying genetic

disorder (eg, Gilbert syndrome or glucose-6-phosphate dehydrogenase deficiency).

Following organ transplantation — Intrahepatic cholestasis is common in transplant

recipients (especially bone marrow and liver). These patients are generally very sick, often

require TPN, and receive multiple potentially hepatotoxic drugs including immunosuppressive

agents, which increase the susceptibility to infection.

In addition to the skin and intestinal epithelium, other target sites of graft-versus-host disease in

bone marrow transplants include the small interlobular bile ducts. The resulting inflammation

and destruction lead to cholestasis. Intensive pretransplantation radiation and chemotherapy

predisposes to the development of veno-occlusive disease of the liver, with cholestasis and liver

failure.

Signs of cholestasis after orthotopic liver transplantation may reflect preservation injury of the

donor organ, an operative complication (bile leak, stricture) [37], and chronic allograft rejection

("vanishing bile duct syndrome"). In addition, cholestasis is occasionally the sole indicator of

acute transplant rejection.

Sickle cell disease — Jaundice in patients with sickle cell disease can result from an

interaction of several factors. The average serum bilirubin concentration in these patients is

higher than normal because of the combination of chronic hemolysis and a mild hepatic

dysfunction. Both unconjugated and conjugated bilirubin accumulate in the plasma. Viral

hepatitis, particularly hepatitis C virus, also may contribute in selected patients. (See "Hepatic

manifestations of sickle cell disease".)

Hepatic crisis, which is usually associated with enlargement and tenderness of the liver, is

thought to result from sequestration of sickled erythrocytes. In severe cases, acute attacks of

intrahepatic cholestasis can occur, leading to very high levels of serum bilirubin and bile salts

[38]. This condition must be differentiated from acute biliary obstruction. Bilirubin microliths,

sludge, calcium bilirubinate stones, and black stones consisting of polymers of bilirubin are

almost universal in patients with sickle cell disease [39]. However, biliary obstruction from these

stones is not common.

Finally, cirrhosis can be caused by chronic vascular lesions [40] or iron overload after multiple

blood transfusions (secondary hemochromatosis). (See "Iron overload syndromes other than

hereditary hemochromatosis".)

Intrahepatic cholestasis of pregnancy — Pruritus, usually occurring in the third trimester of

pregnancy but sometimes earlier, typically heralds cholestasis which may evolve into frank

jaundice [41] and may be associated with an increased frequency of stillbirths and prematurity

[42]. All the pathologic changes disappear following delivery. (See "Intrahepatic cholestasis of

pregnancy".)

Intrahepatic cholestasis of pregnancy is thought to be inherited, although the mode of

inheritance is not well defined [43]. A possible relationship to benign recurrent intrahepatic

cholestasis has been postulated (see "Gilbert syndrome and unconjugated hyperbilirubinemia

due to bilirubin overproduction"). It is of crucial importance to distinguish this entity from other

potentially lethal liver disorders in pregnancy such as acute fatty liver and the HELLP syndrome.

(See "Acute fatty liver of pregnancy".)

End-stage liver disease — The hallmarks of end-stage liver disease and cirrhosis, regardless

of its etiology, include jaundice with an elevation of both conjugated and unconjugated bilirubin

as well as portal hypertension and decreased hepatic synthetic function.

Hepatocellular injury — A partial overview of disorders causing hepatocellular jaundice is

presented in the table (table 4). These conditions cannot always be separated clearly from the

cholestatic syndromes because of the variability in presentation of these diseases. There are,

however, characteristic differences between the two mechanisms of hepatic disease.

Hepatocellular injury is typically characterized by the release of intracellular proteins and small

molecules into the plasma. Thus, in contrast to cholestatic syndromes, the elevations in serum

conjugated and unconjugated bilirubin and bile salts are accompanied by elevations in the

serum concentrations of hepatocellular proteins, such as aspartate aminotransferase (AST),

alanine aminotransferase (ALT), and glutathione S-transferase (GST).

With chronic hepatocellular injury, the biochemical profile changes over time as the liver injury

progresses to cirrhosis and liver failure. The elevation of liver enzymes, a marker of active liver

injury, becomes less prominent or even disappears. The primary manifestations at this time

result from impaired hepatic protein synthesis (eg, hypoalbuminemia and a prolonged

prothrombin time) and impaired excretory function, leading to jaundice.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain

language, at the 5th to 6th grade reading level, and they answer the four or five key questions a

patient might have about a given condition. These articles are best for patients who want a

general overview and who prefer short, easy-to-read materials. Beyond the Basics patient

education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10th to 12th grade reading level and are best for patients who want in-depth information

and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print

or e-mail these topics to your patients. (You can also locate patient education articles on a

variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient information: Jaundice in adults (The Basics)" and "Patient

information: Gilbert’s syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●An approach to patients with abnormal liver biochemical tests is presented separately.

(See "Approach to the patient with abnormal liver biochemical and function tests".)

●For clinical purposes, the predominant type of bile pigments in the plasma can be used to

classify hyperbilirubinemia into two major categories, conjugated and unconjugated (table

1 and algorithm 1A-B).

●Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin

uptake, and impaired bilirubin conjugation, are mainly responsible for unconjugated

hyperbilirubinemia.

●A variety of acquired disorders with conjugated hyperbilirubinemia can be categorized

according to their histopathology and pathophysiology: biliary obstruction (extrahepatic

cholestasis), intrahepatic cholestasis, and hepatocellular injury. The differential diagnosis

of extrahepatic and intrahepatic hyperbilirubinemia is summarized in the tables (table

2and table 3).Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)AuthorLawrence S Friedman, MDSection EditorSanjiv Chopra, MD, MACPDeputy EditorAnne C Travis, MD, MSc, FACG, AGAFDisclosures: Lawrence S Friedman, MD Other Financial Interest: Elsevier [Gastroenterology (Royalties from textbooks)]; McGraw-Hill [Gastroenterology (Royalties from textbooks)]; Wiley [Gastroenterology (Royalties from textbooks)]. Sanjiv Chopra, MD, MACP Nothing to disclose. Anne C Travis, MD, MSc, FACG, AGAF Equity Ownership/Stock Options: Proctor & Gamble [Peptic ulcer disease, esophageal reflux (omeprazole)].

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2015. | This topic last updated: Jun 02, 2014.

INTRODUCTION — A number of blood tests are available that reflect the condition of the liver.

The most common tests used in clinical practice include the serum aminotransferases, bilirubin,

alkaline phosphatase, albumin, and prothrombin time. These tests are often referred to as "liver

function tests," although this term is somewhat misleading since most do not accurately reflect

how well the liver is functioning, and abnormal values can be caused by diseases unrelated to

the liver. In addition, these tests may be normal in patients who have advanced liver disease.

Several specialized tests have also been developed (such as indocyanine green clearance),

which, although uncommonly used in clinical practice, can measure specific aspects of hepatic

function.

Despite their limitations, liver biochemical and function tests have many applications in clinical

medicine:

●They provide a noninvasive method to screen for the presence of liver disease. The

serum aminotransferases, for example, were used in the past to screen all blood donors in

the United States for the presence of transmissible viruses before specific viral tests were

available.

●They can be used to measure the efficacy of treatments for liver disease (such as

immunosuppressant agents for autoimmune hepatitis). (See "Autoimmune hepatitis:

Treatment".)

●They can be used to monitor the progression of a disease such as viral or alcoholic

hepatitis.

●They can reflect the severity of liver disease, particularly in patients who have cirrhosis.

As an example, the Child-Pugh score, which incorporates the prothrombin time and serum

bilirubin and albumin concentrations, can predict survival (table 1).

The pattern of abnormalities on these tests is more accurate than any of the individual tests.

Elevation of serum aminotransferases indicates hepatocellular injury, while elevation of the

alkaline phosphatase indicates cholestasis. Recognition of patterns that are consistent with

specific diseases can prompt appropriate additional testing.

The liver biochemical and function tests that are used commonly in clinical practice and that are

used occasionally for specific circumstances can be categorized as follows:

●Tests that detect injury to hepatocytes – Most of these tests measure the activity of

hepatic enzymes, such as the aminotransferases, in the circulation. These enzymes are

normally intracellular, but are released when hepatocytes are injured. (See "Liver

biochemical tests that detect injury to hepatocytes".)

●Tests of the liver's capacity to transport organic anions and metabolize drugs – These

tests measure the liver's ability to clear endogenous or exogenous substances from the

circulation. The best studied include serum measurements of bilirubin, bile acids, caffeine,

and lidocaine metabolites, a variety of breath tests, and clearance tests such as

bromsulphalein (BSP) and indocyanine green (ICG).

●Tests of the liver's biosynthetic capacity – The most commonly performed tests to assess

the biosynthetic capacity of the liver are the serum albumin and the prothrombin time

(which requires the presence of clotting factors produced in the liver). Other tests which

have been use are the serum concentrations of lipoproteins, ceruloplasmin, ferritin, and

alpha 1-antitrypsin.

●Tests that detect altered immunoregulation or viral hepatitis – These tests include the

immunoglobulins, hepatitis serologies, and specific autoantibodies. Most of these

substances are proteins made by B lymphocytes, not by hepatocytes. However, some are

quite specific for certain liver diseases, such as antimitochondrial antibodies in primary

biliary cirrhosis. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary

cirrhosis".)

This topic will review the role of the serum albumin and prothrombin time in the evaluation of the

liver's biosynthetic capacity. The other categories of liver function tests are discussed

separately. (See "Approach to the patient with abnormal liver biochemical and function

tests" and "Liver biochemical tests that detect injury to hepatocytes" and "Enzymatic measures

of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl

transpeptidase)" and "Clinical aspects of serum bilirubin determination" and "Tests of the liver's

capacity to transport organic anions and metabolize drugs".)

SERUM PROTEINS — The liver is the major site where serum proteins are synthesized. These

include albumin and the coagulation factors.

Albumin — Albumin is quantitatively the most important plasma protein. Approximately 300 to

500 g of albumin is distributed in the body fluids, and the average adult liver synthesizes

approximately 15 g per day (200 mg/kg per day). The synthesis rate can double in situations in

which there is rapid albumin loss or a fall in the serum albumin concentration.

The serum albumin concentration reflects the rate of synthesis, rate of degradation, and volume

of distribution. Albumin synthesis is regulated by a variety of factors, including nutritional status,

serum oncotic pressure, cytokines, and hormones [1,2]. How these factors operate on a cellular

level is not precisely known but may involve the formation of albumin messenger ribonucleic

acid (mRNA) polysomes within the liver [1-3]. Substances that stimulate albumin synthesis

increase the efficiency of this process. By contrast, inhibitory substances associated with

inflammatory states, such as tumor necrosis factor and interleukin-1, impede albumin synthesis

[4-6].

Little is known about the site of degradation of albumin. The half-life of albumin in serum is

approximately 20 days, with 4 percent of the total albumin pool being degraded daily.

Clinical significance — Hypoalbuminemia does not always reflect the presence of hepatic

synthetic dysfunction since a variety of other conditions may be responsible including systemic

inflammation, the nephrotic syndrome, and malnutrition. Some general observations can be

made in patients with liver disease who do not appear to have these other disorders:

●Serum albumin concentrations tend to be normal in acute viral hepatitis, drug-related

hepatotoxicity, and obstructive jaundice. The possibility of chronic liver disease should be

considered when the serum albumin concentration is below 3 g/dL (30 g/L) in these

patients.

●Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis. The fall in

albumin concentration usually reflects severe liver damage with reduced albumin

synthesis [7]. An exception may occur in patients with ascites who may become

hypoalbuminemic despite good hepatic synthetic function because of the often marked

increase in plasma volume [8].

The serum albumin concentration should not be measured for screening in patients in whom

there is no suspicion of liver disease. This was illustrated in a study that included 449 patients

seen in a general medical practice in whom serum albumin was measured routinely; 13 percent

had an abnormal value, which was found to be clinically significant in only two patients [9].

Serum albumin levels persistently above the laboratory's reference range are usually observed

in normal people who are at the extreme right of the bell-shaped curve. Acute

hyperalbuminemia is seen most commonly in patients with volume depletion, in whom it is often

associated with hemoconcentration as well. A case report described hyperalbuminemia in a

patient consuming a high-protein diet [10]. Hyperalbuminemia is also theoretically possible in

patients with genetic variants that prolong the half-life of albumin in serum.

Coagulation factors — The liver is the major site of synthesis of 11 blood coagulation proteins.

These include

●Factor I (fibrinogen)

●Factor II (prothrombin)

●Factor V

●Factor VII

●Factor IX

●Factor X

●Factor XII

●Factor XIII

Clotting factor deficiency frequently occurs during the course of liver disease. These proteins

can be measured individually or indirectly by more general measures of clotting ability such as

the prothrombin time.

Clinical significance — A prolonged prothrombin time is not specific for liver disease, since it

can result from various congenital or acquired conditions including consumption of clotting

factors (such as disseminated intravascular coagulation or severe gastrointestinal bleeding) and

certain drugs. When these conditions have been excluded, a prolonged prothrombin time

usually reflects one of two disorders:

●A deficiency of vitamin K, which may be induced by inadequate dietary intake, prolonged

obstructive jaundice, intestinal malabsorption, or the administration of antibiotics that alter

the gut flora. In such cases, the prothrombin time typically returns to normal within 24

hours after a single parenteral injection of vitamin K. This response is particularly helpful

diagnostically when evaluating patients who are jaundiced.

●Poor utilization of vitamin K due to advanced parenchymal liver disease. Vitamin K

supplementation is generally ineffective in this setting.

The prothrombin time does not accurately reflect the coagulation status of patients with cirrhosis

[11] or correlate with the risk of bleeding because of concomitant reductions in the hepatic

synthesis of anti-hemostatic factors [12]. (See "Coagulation abnormalities in patients with liver

disease".)

However, the magnitude of elevation of the prothrombin time above control does correlate with

prognosis in some conditions. As an example, an elevation more than five seconds above

control should raise concern about a fulminant course in patients who have acute viral, toxic, or

alcoholic hepatitis [13,14]. A prothrombin time above 100 sec is considered an indication for

liver transplantation [13]. However, some patients, particularly those who

have acetaminophen overdose, recover despite marked elevations in the prothrombin time. A

progressive decline in the prothrombin time in such patients usually heralds recovery.

(See "Acute liver failure in adults: Etiology, clinical manifestations, and

diagnosis" and"Acetaminophen (paracetamol) poisoning in adults: Pathophysiology,

presentation, and diagnosis" and "Acetaminophen (paracetamol) poisoning in adults:

Treatment".)

International normalized ratio — The international normalized ratio (INR) is often used to

express the degree of anticoagulation in patients receiving warfarin. The INR standardizes

prothrombin time measurement based upon characteristics of the thromboplastin reagent used

in the laboratory. This helps to eliminate variability between measurements in which different

thromboplastin reagents are used and thereby assures a stable level of anticoagulation.

In contrast to its use in patients on warfarin, the INR may not be the best expression of

coagulation derangement in patients with liver failure, especially if the same thromboplastin

reagents are not consistently used for measurement [15,16]. This was illustrated in a study in

which various expressions of the prothrombin time (seconds above control, ratio to control,

activity percentage, and INR) were evaluated in 27 patients with chronic or acute liver failure

compared with controls [15]. Only the activity percentage expression eliminated variability in the

prothrombin time results in individual patients when using different thromboplastin reagents.

This observation implies that, in an individual patient with liver failure, interpretation of changes

in the INR may only be accurate when the same thromboplastin is used. Furthermore,

comparison of the degree of synthetic dysfunction using the INR in patients who underwent

testing at centers using different thromboplastin reagents may not be valid [17,18]. This may be

particularly relevant when prioritizing patients for liver transplantation [18]. (See "Model for End-

stage Liver Disease (MELD)".)

A new standardization method for the INR is needed to make the INR more applicable in

patients with liver disease. At least two such modifications have been proposed, both of which

reduced variability when used for calculation of the MELD score [19,20]. (See "Coagulation

abnormalities in patients with liver disease".)

Des-gamma-carboxy prothrombin — The synthesis of factors II, VII, IX, and X requires

vitamin K for the addition of carboxylic acid moieties to the gamma position of glutamic acid

residues in these proteins [21]. (See "Vitamin K and the synthesis and function of gamma

carboxyglutamic acid".) Gamma carboxylation permits these proteins to bind calcium, which is

necessary for them to function normally. An abnormal prothrombin form (des-gamma-carboxy

prothrombin) is released in the absence of vitamin K, in the presence of vitamin K antagonists

such as warfarin, and by certain tumors, such as hepatocellular carcinoma (HCC). Des-gamma-

carboxy prothrombin is produced by the malignant hepatocyte which appears to acquire a

posttranslational defect in the vitamin K-dependent carboxylase system [22]. The serum

concentration of des-gamma-carboxy prothrombin has been evaluated for screening patients at

risk for hepatocellular carcinoma but appears to have lower sensitivity than alpha fetoprotein

(AFP) for tumors <3 cm. (See "Clinical features and diagnosis of primary hepatocellular

carcinoma".)

SUMMARY AND RECOMMENDATIONS

●The most commonly performed tests to assess the biosynthetic capacity of the liver are

the serum albumin and the prothrombin time (which is based upon the presence of clotting

factors produced in the liver). Other tests which have been used are the serum

concentrations of lipoproteins, ceruloplasmin, ferritin, and alpha 1-antitrypsin.

●The liver is the major site where serum proteins are synthesized. These include albumin

and the coagulation factors. The clinical significance of low and high values is described

above. (See 'Serum proteins' above.)

●In contrast to its use in patients on warfarin, the international normalized ratio (INR) may

not be the best expression of coagulation derangement in patients with liver failure.

(See"Coagulation abnormalities in patients with liver disease" and 'International

normalized ratio' above.)